-> 


IMAGE  EVALUATION 
TEST  TARGET  (MT-3) 


1.0 


I.I 


11.25 


itt  IM 

ly 


12.2 


SI    |£0    12.0 


U   1 1.6 


Hiotographic 

Sdences 

Carporation 


33  Wnr  MAIN  STtHT 

WIUTM.N.V.  t4SN 

(7U)I73-4S03 


CIHM/ICMH 

Microfiche 

Series. 


CIHIVI/ICMH 
Coliection  de 
microfiches. 


Canadian  Inatituta  for  Hiatorical  Microraproductiona  /  Inatitut  Canadian  da  microraproductiona  hiatoriquaa 


:\ 


Tachnical  and  Bibliographic  Notaa/Notas  tachniquaa  at  bibliographiquaa 


Tha  Inatituta  haa  attamptad  to  obtain  tha  baat 
original  copy  availabia  for  filming.  Paaturaa  of  tbia 
copy  whieh  may  ba  bibllographically  uniqua. 
which  may  altar  any  of  tha  imagaa  in  tha 
raproduction,  or  whieh  may  aignificantiy  changa 
tha  uaual  mathcd  of  filming,  ara  chackad  balow. 


HColourad  covara/ 
Couvartura  da  coulaur 


nn   Covara  damagad/ 


D 


Couvartura  andommagia 

Covara  raatorad  and/or  iaminatad/ 
Couvartura  raataur^a  at/ou  pallicuMa 


n~|   Covar  titia  miaaing/ 


La  titra  da  couvartura  manqua 


□   Colourad  mapa/ 
Cartaa  g4ographiquaa  an  coulaur 


D 


Colourad  ink  (i.a.  othar  than  Wua  or  black)/ 
Encra  da  coulaur  (i.a.  autra  qua  blaua  ou  noira) 


r~~|   Colourad  plataa  and/or  illuatrationa/ 


D 
D 


D 


D 


Planchaa  at/ou  illuatrationa  9n  coulaur 


Bound  whh  othar  matarial/ 
RalM  avac  d'autraa  docunanta 


Tight  binding  may  cauaa  ahadowa  or  diatortion 
along  intarior  margin/ 

LaraUura  aarrte  paut  cauaar  da  I'ombra  ou  da  la 
diatocalon  la  kHig  da  la  marga  intiriaura 

Blank  laavaa  addad  during  raatoration  may 
appaar  within  tha  taxt.  Whanavar  poaaibla.  thaaa 
hava  baan  omittad  from  filming/ 
II  aa  paut  qua  cartainaa  pages  blanchaa  ajoutiaa 
lora  d'una  raatauration  appaidiaaant  dana  la  taxta, 
mala,  loraqua  eala  4tait  poaaibla.  caa  pagaa  n'ont 
paa  At*  film4aa. 

Additional  oommanta:/ 
Commantairaa  auppiimantairaa: 


L'Inatitut  a  microfiimi  la  maiilaur  axamplaira 
qu'il  lui  a  *t*  poaaibla  da  aa  procurer.  Laa  details 
da  cat  axamplaira  qui  aont  paut-Atra  uniquaa  du 
point  da  vua  bibliographiqua.  qui  pauvant  modifiar 
una  imaga  raproduite.  ou  qui  pauvant  axigar  una 
modification  dana  la  mithoda  normaia  da  filmaga 
aont  indiquia  d-daaaoua. 


D 


n 


Thia  itam  la  filmad  at  tha  raduction  ratio  chackad  balow/ 

Ca  documant  aat  film*  au  taux  da  reduction  indiquA  ci-daaaoua. 


Colourad  pagaa/ 
Pagaa  da  coulaur 


□   Pagaa  damagad/ 
Pagaa  andommagAaa 

□   Pagaa  raatorad  and/or  Iaminatad/ 
Pagaa  raataurAaa  at/ou  pailicuiAaa 

0   Pagaa  diacolourad.  stainad  or  foxad/ 
Pagaa  dAcoloriaa,  tachatAas  ou  piqui 


Pagaa  dAcolorAaa,  tachatAas  ou  piquAaa 

Pagaa  datachad/ 
Pagaa  dAtachAaa 

Showthrounhy 
Tranaparanca 

Quality  of  prin 

QualitA  InAgala  da  I'impraaaion 

Includaa  aupplamantary  matarii 
Comprand  du  matArial  aupplAmantaira 

Only  adition  availabia/ 
Saula  Aditian  diaponibia 


|~n   Pagaa  datachad/ 

EShowthrounh/ 
rn   Quality  of  print  variaa/ 
|~n   Includaa  aupplamantary  material/ 
r~1   Only  adition  availabia/ 


Pagaa  wholly  or  partially  obscured  by  errata 
slipa.  tissuea,  etc..  hava  been  refilmed  to 
enaura  the  beat  possible  image/ 
Lea  pagea  totalement  ou  partiellement 
obacurcias  par  un  fauiiiet  d'errata.  una  pelure, 
etc..  ont  AtA  filmAes  A  nouveau  da  fa^on  A 
obtanir  la  mailleure  imaga  possible. 


10X 

14X 

1IX 

22X 

MX 

»x 

7 

12X 

IfX 

aox 

MX 

»X 

32X 

Th«  copy  fllmcd  hw  hn  b««n  raproduead  thanks 
to  the  aanaroaity  off: 

MMlieal  Library 
MoQill  Univmity 
MontrMM 


Tho  imogot  appoaring  hara  ara  tha 
posaibia  conaidaring  tha  condition 
off  tha  originai  copy  and  in  Icaaping 
ffliming  contract  spacifflcationa. 


quaiity 
lagibility 
tha 


L'axamplaira  ffllm*  fut  raproduit  grica  i  la 
g4niroaitA  da: 

MMUeii  Library 
RMoQill  Urrivanity 


Laa  imagaa  auivantaa  ont  4t*  raproduitaa  avac  la 
plua  grand  aoin,  compta  tanu  da  la  condition  at 
da  ia  nattati  da  I'axamplaira  fiimA,  at  an 
confformitA  avac  laa  conditiona  du  contrat  da 
ffilmaga. 


Original  coplaa  in  printad  papar  covara  ara  fiimad 
baginning  with  tha  ffront  covar  and  anding  on 
tha  laat  paga  with  a  printad  or  iiiuatratad  impraa- 
slon,  or  tha  back  covar  whan  appropriata.  All 
othar  originai  coplaa  ara  ffiimad  baginning  on  tha 
ffirat  paga  with  a  printad  or  iiiuatratad  Impraa- 
aion.  and  anding  on  tha  laat  paga  with  a  printad 
or  iiiuatratad  impraaaion. 


I.aa  axampiairaa  origlhaux  dont  la  couvartura  an 
papiar  aat  imprimte  aont  fflintte  an  comman9ant 
par  la  pramiar  plat  at  an  tarminant  aoit  par  la 
danMra  paga  qui  comporto  una  amprainta 
dimpraaaion  ou  dlNuatration,  aoit  par  la  sacond 
plat,  aalon  la  caa.  Toua  laa  autraa  axampiairaa 
originaux  aont  fllmte  an  commandant  par  la 
pramMra  paga  qui  comporta  una  amprainta 
dimpraaaion  ou  dlNuatration  at  an  tarminant  par 
la  damlAra  paga  qui  comporta  una  taUa 
amprainta^ 


Tha  last  racordad  fframa  on  aach  microffieha 
shaH  contain  tha  aymbol  ^^  (moaning  "CON- 
TINUED"), or  tho  aymbol  ▼  (moaning  "END"). 
whiclMvar  appHaa. 


Un  daa  symbolaa  auivanta  apparattra  aur  la 
damlAra  Imaga  da  chaqua  microffieha,  aaton  la 
caa:  la  aymbola  -^  signiffia  "A  8UIVRE",  la 
aymbola  ▼  aigniffia  "FIN". 


Mapa.  plataa.  charta,  ate.,  may  ba  ffiimad  at 
diffffarant  raduction  ratloa.  Thoaa  too  larga  to  ba 
antiraly  Inciudad  in  ana  axpoaura  ara  ffiimad 
baginning  in  tha  uppar  lafft  hand  comar.  lafft  to 
right  and  top  to  bottom,  aa  many  fframaa  aa 
raquirad.  Tha  ffoliowtoig  diagrama  INuatrato  tha 
mathod: 


l.aa  cartaa.  planchaa.  tablaaux,  ate.,  pauvam  Atra 
ffilmAa  i  daa  taux  da  rMuction  diffffAranta. 
Loraqua  la  document  aat  trap  grand  pour  Atra 
raproduit  an  un  saui  clicliA.  11  eet  ffNmA  A  partir 
da  i'angia  aupAriaur  gauche,  da  gaueha  A  droita. 
at  da  haut  an  baa.  an  prenant  la  nombra 
d'imagae  nAceeeaira.  Lea  diagrammae  auivanta 
llluatrent  la  mAthoda. 


1 

2 

3 

1 

2 

3 

4 

5 

6 

INFLAMMATION 


AN  ARTICLE  BY  J.  G.  ADAMI, 
M.A.,  M.D.,  REPRINTED  FROM 
PROF.  CLIFFORD  ALLBUTT'S 
NEW  SYSTEM   OF  MEDICINE 


FOR    PRIVATE    CIRCULATION 


%|P 


THE  MACMILLAN  COMPANY 
NEW  YORK 

J896 


\ 


si- 


Copyright,  1896, 
By  MACMILLAN  AND  CO. 


<• 


3.  8.  Cuihiitff  8i  Co.  -  licrwick  &  Smltli 
Nurwodd  MaflR.  ir.R.A. 


\i 


/ 


c 


/ 


PREFACE 


Believing  that  it  will  be  advantageous  to  the  students  attend- 
ing my  course  to  be  able  to  obtain  for  themselves  this  study  or 
essay  upon  Inflammation,  I  have  begged  the  publishers  of  Professor 
Allbutt's  New  System  of  Medicine  to  grant  me  reprints,  especially 
for  the  use  of  McGill  students.  I  would  here  record  my  apprecia- 
tion of  the  favour  shown  to  me  by  The  Macmillan  Company  in 
departing  from  ordinary  usage  and  acceding  so  willingly  to  my 
request.  . 

J.  GEORGE  ADAMI 
Patiiolooical  Laboratory, 
McGiLL  Univbrsity,  September,  1896. 


INFLAMMATION* 

Part  I. — A  General  Survey  of  the  Process  of  Inflammation 

Chapter  1.  Introduction. — Chapter  2.  The  Comparative  Patliolo^y  of  Inflamma' 
tion.  —  Chapters.  Tlie  Main  Forms  of  the  Process  of  Acute  Iiitiummatiuu  it  the 
Higher  Animals. 

Part  II.  —  The  Factors  in  the  Inflammatory  Process 

Chapter  1,  On  the  Part  played  by  the  Leucocytes.  —  Chapter  2.  On  tlio  Inflamma- 
tory Exudation.— Chapter  3.  On  the  Part  played  by  the  Blood-Vessols.  —  Chap- 
ter 4.  On  the  Passage  of  Corpuscles  out  of  the  Vessels.  —  Chapter  5.  On  the  Part 
played  by  the  Nervous  System.  —  Chapter  6.  On  the  Part  played  by  the  Cells  of 
the  Tissue.  —  Chapter?.  On  Fibrous  Hyperplasia  and  its  Relationship  to  lutiam- 
mation. 

Part  III 

Chapter  1.  On  Classification. — Chapter  2.  On  Systemic  Changes  accompanying 
Local  Injury  and  Litlammation.  —  Chapter  3.  Conclusion.  —  Biblioqrapuy. 

PART  I.  —  A  General  Survey  of  the  Process  of  Inflammation 

Chapter  1.  —  Introduction 

Definition  of  Inflammation.  —  It  is  usual  to  begin  the  description  of 
a  morbid  process  by  defining  that  process.     In  the  case  of  infianima- 


1  The  following  article  is  an  attempt  to  bring  into  order  the  very  numerous  recent 
researches  up<jn  the  inflammatory  process,  and  to  show  whither  they  appear  to  tend  ;  it 
pretends  in  no  wise  to  be  a  complete  treatise  upon  the  development  of  our  knowledge  of 
the  subject.  Space  alone  has  forbidden  that  I  should  trace  the  full  history.  I  would 
therefore  strongly  urge  that  as  a  currective  other  works  be  consulted  in  which  the  earlier 
theories  are  treated  at  length:  more  esiiecially  would  I  rcconiMicnd  (as  throwing  light 
upon  the  progress  of  our  knowledge)  Professor  Burdou-Saudersou's  article  upon  luflam- 
matiou  iu  Holmes's  Hysttm  of  Hunjery. 


INFLAMMA  TION 


55 


tion,  however,  we  have  to  deal  with  a  process  so  complex,  so  modified  by 
modifications  of  the  many  factors  involved,  and  so  variable  in  its  manifes- 
tations according  to  the  variety  of  its  causes  and  the  region  of  incidence, 
that  the  attempt  to  define  it  has  proved  a  pitfall  to  pathologist  after 
pathologist ;  moreover,  to  advance  a  definition  of  the  process  at  the  begin- 
ning of  this  article  in  terms  differing  to  any  considerable  extent  from 
those  employed  by  previous  writers,  would  demand  a  criticism  of  the  many 
previous  attempts ;  and  in  order  that  the  definition  put  forward  be  duly 
supported,  woidd  necessitate  an  essay  covering  the  whole  field  about  to 
be  traversed.  I  shall  then  leave  definition  to  the  end,  until  I  have 
marshalled  my  facts,  and  have  brought  into  line  all  that  appears  to  me 
necessary  for  a  correct  understanding  of  the  process.  The  definition 
must  be  the  summing  up  of  the  subject,  not  the  introduction  thereto. 

Use  of  the  Name.  —  Yet,  in  the  meantime,  inasmuch  as  divergent 
views  are  held  of  the  limitations  of  the  use  of  the  name  inflammation, 
a  few  words  of  introduction  are  advisable. 

Two  courses  are  before  us :  either  to  employ  the  name  strictly  in 
accordance  with  the  primitive  definition,  and  thus  only  to  include  as 
cases  of  inflammation  those  states  in  which  there  are  present  redness, 
swelling,  heat  and  pain,  rigidly  excluding  all  cases  in  which  these  cardinal 
symptoms  are  not  present;  or,  on  the  other  hand,  departing  from 
tradition,  to  include  as  inflammations  all  those  morbid  processes  which 
seem  to  have  a  cause  and  progress  inseparable  from  and  merging 
into  the  cause  and  progress  of  the  state  characterised  by  the  classical 
symptoms.  The  first  course  is  impossible ;  it  is  as  though  one  were  to 
declare  that  red  phosphorus  is  not  phosphorus  because  in  externals 
generally  it  does  not  agree  with  the  definition  of  the  yellow  form  made 
years  before  the  allotropic  modification  was  discovered.  We  are  now 
well  agreed  that  of  the  classical  symptoms,  one,  two  or  three  may  be 
unrecognisable,  and  in  fact  absent ;  and  yet  the  condition  of  inflamma- 
tion be  undoubtedly  present.^ 

The  second  is  the  only  possible  course,  that,  namely,  which  associates 
all  those  states  which  under  suitable  conditions  may  result  in  the  pro- 
duction of  the  four  classical  symptoms,  and  moreover  originate  from  a 
common  cause.  Holding  this  view,  it  will  in  the  meantime  be  well  for 
me,  in  order  to  afford  a  starting-point  for  the  description  and  discus- 
sion of  the  subject,  to  select  from  the  many  definitions  one  which  is 
based  not  on  symptomatology,  but  upon  aetiology,  and  indicates  a  common 
origin  for  all  cases  of  inflammation.  I  would  select  that  which  in  this 
country  has  received  the  most  cordial  support,  the  definition  given  by 
Professor  Burdon-Sanderson  in  his  well-known  article  in  Holmes's  System 
of  Surgery :  "  The  process  of  inflammation  is  the  succession  of  changes 

1  A  course  allied  to  this  has  found  favour  of  late  years  among  sundry  surgical  patholo- 
gists, who  would  limit  the  use  of  the  term  to  those  cases  and  those  only  in  which  the  classi- 
cal symptoms,  or  the  majority  thereof,  are  present  and  associate<l  with  suppuration, —  they 
urge  with  HUter  that  iuHammation  only  occurs  when  pyogenic  micro-org.anismsarc  present, 
and  state  that  when  a  wound  heals  aseptically  it  heals  witliout  intlamniati(m.  This  niodi- 
liod  course  is  equally  imi>ossible ;  pyugeuesis  must  uot  be  cuufouuded  with  iutlammatiou. 


s« 


SYSTEM  OF  MEDICINE 


which  occurs  in  a  living  tissue  when  it  is  injured,  provided  that  the  injury 
is  not  of  such  a  degree  as  at  once  to  destroy  its  structure  and  vitality." 
This  definition  includes  too  much.  The  haemorrhage  that  occurs  in 
the  liver  when  it  is  injured,  and  the  changes  that  there  occur  in  the 
extravasated  red  corpuscles,  are  scarcely  to  be  classed  among  inflam- 
matory phenomena ;  the  atrophic  changes  which  occur  in  the  retina,  when 
through  injury  it  becomes  detached,  are  due  mainly  to  malposition 
and  disuse  racher  than  to  the  primary  trauma.  But,  as  Dr.  Burdon 
Sanderson  has  pointed  out,  the  definition  has  this  great  advantage, 
that  stating  the  cause,  it  clearly  recognises  inflammation  as  a  process 
and  not  as  a  state.  The  external  manifestations  of  this  process  under 
favourable  conditions — where  the  region  injured  is  a  loose  and  vascular 
tissue,  and  where  the  injury  is  sufficiently  severe  or  extensive  —  are  red- 
ness, swelling,  and  heat  with  pain :  redness  from  the  congestion  of  the 
vessels ;  swelling  from  the  exudation  of  fluid  and  corpuscles  from  the 
congested  vessels ;  heat  from  the  increased  amount  of  blood  in  the  region, 
and  pain  from  the  pressure  upon  and  irritation  of  the  terminations  of  the 
nerves  in  the  region.  To  these  four  symptoms  may  be  added  a  fifth, 
disturbance  of  function  brought  about  by  this  departure  from  the 
normal  condition  of  the  region.  Under  unfavourable  conditions  —  where 
the  region  injured  is  dense  or  less  vascular,  or  where  the  injury  is  less 
severe  —  one  or  all  of  these  symptoms  may  seem  wanting ;  nevertheless 
a  minute  examination  of  the  tissues  will  show  the  same  succession  of 
changes  as  in  the  former  case. 


Chapter  2.  —  The  Comparative  Pathology  op  Inflammation 


Accepting,  then,  this  working  definition,  in  order  to  arrive  at  a  due 
comprehension  of  the  succession  of  changes  which  we  take  to  constitute 
the  inflammatory  process,  it  will  be  well  with  Metschnikoff '  to  institute 
a  series  of  observations  upon  the  reaction  to  injury  exhibited  throughout 
the  animal  kingdom  from  the  lowest  forms  upwards  to  man.  By  this 
means  we  shall  be  enabled  to  determine  what  factors  in  the  inflammatory 
process  are  from  their  constancy  of  primary  importance ;  what  are  com- 
mon and  essential,  and  what  are  superadded  in  the  higher  animals. 

The  Response  to  Injury  among  the  Protozoa.  —  Beginning  our  study 
with  the  lowest  and  simplest  forms  of  life  —  forms  so  lowly  that 
they  have  been  regarded  both  as  animals  and  as  plants  —  we  find  even 
here  phenomena  accompanying  the  reaction  to  injury  which  throw  light 
upon  the  inflammatory  process  as  seen  in  the  higher  animals.  Taking  as 
an  example  the  amoeba,  we  find,  in  the  first  place,  that  the  nucleus  plays  an 

1  Tho  succeodinp;  paragraphs  are  of  necessity  very  largely  an  epitome  of  sundry  por- 
tions of  M.  Metschnikoft's  most  pregnant  work  upon  the  comparative  pathology  of  inflam- 
mation. By  comparing  tliem  with  the  work  in  question,  it  will,  however,  ho  seen  that 
they  depart  from  it  in  several  points ;  more  esi)ecially  in  dwelling  upon  the  extracellular 
activity  of  the  wandering  culls,  and  in  hriiiging  more  pruminontly  forward  tho  rospousu 
to  injury  on  tho  part  of  tho  llxed  cells. 


INFLAMMA  TION 


57 


important  part  in  this  reaction.  If,  as  Metschnikoff  lias  shown,  one  of 
the  larger  amoebae  be  cut  in  two,  the  region  of  injury  becomes  rapidly 
indistinguishable — the  protoplasm  of  each  moiety  closes  up,  leaving  no 
mark  or  scar :  but  of  the  two  parts  that  which  retains  the  nucleus  grows 
and  proliferates ;  the  other  disintegrates  in  a  longer  or  shorter  time.  Or 
injury  may  induce  changes  in  the  protoplasm  of  the  entire  amoeba:  thus, 
Miss  Greenwood  points  out  that,  without  necessarily  bringing  about 
death,  the  inLorrupted  current  or  an  aqueous  solution  of  thymol  leads  to 
a  process  of  exudation  or  extrusion  of  clear  hyaline  spheres,  or  of  spheres 
holding  crystals  and  granules,  from  the  surface  of  the  organism — a  pro- 
cess resembling  that  occasionally  seen  in  the  cells  of  an  inflammatory 
area  in  higher  animals.  Nor  is  this  all;  apart  from  changes  in  the 
structure  of  these  unicellular  animals,  differences  may  be  seen  in  the 
behaviour  of  amoebae  towards  foreign  bodies.  It  would  seem,  accord ' .  g 
to  Le  Dantec,  that  amoebse  ingest  non-irritating  foreign  substances  in- 
differently, provided  they  be  sufficiently  small.  Around  each  particle  so 
ingested  a  vacuole  is  formed,  and  the  fluid  in  this  becomes  increasingly 
acid,  and  at  the  same  time  digestive.  Kiukenberg,  lieinke  and  Miss 
Greenwood  have  conclusively  proved  these  and  similar  food  vacuoles  in 
the  amoeba  and  other  Protozoa  to  contain  a  pepsine  or  digestive  ferment, 
which,  as  Le  Dantec  has  shown  by  very  delicate  tests,  exerts  its  action 
in  an  acid  medium  (the  general  protoplasm  of  the  cell  body  being  alkar 
line);  this  digestive  process  leads  to  the  solution  of  food  stuff's,  pre- 
paring them  to  be  taken  up  by  the  protoplasm  of  the  organism.  If  the 
foreign  substances  be  incapable  of  digestion  they  are  sooner  or  later  ex- 
truded. It  is  by  this  fonn;ition  of  digestive  vacuoles  that  the  anutba  acts 
upon  and  destroys  bacteria,  diatoms,  and  other  microbes  ingested  by  it. 
There  are,  however,  microbic  forms  around  which  it  would  seem  that  no 
proper  vacuolation  is  developed,  or  if  developed,  the  acid  digestive  fluid 
is  neutralised  by  substances  discharged  from  the  parasites ;  where  this 
is  the  case,  instead  of  destruction  there  is  continuance  of  vitality  and 
actual  multiplication  of  the  invading  or  parasitic  form,  leading  to  the 
eventual  death  of  the  amct'ba.  Metschnikoff  has  observed  this  chain  of 
events  in  one  of  the  anui'bie  which  ingests  and  becomes  tlie  host  of  a 
minute  rounded  form,  the  ^^licrospha'ra.  IMienomena  of  like  nature 
may  bo  observed  among  the  ciliate  and  flagellate  infusorifi.  While 
these  phenomena  may  primarily  bo  regarded  as  the  method  employed 
oy  the  IM'otozoa  for  the  assiniihition  of  food  stuff's,  tlicy  also  are  clearly 
the  means  whereby  the  Proto/oa  defend  themselves  against  living 
organisms  which  have  gained  entrance  into  them,  and  thus  foriu  tho 
reaction  to  possible  injury ;  for  when  in  certain  eases  the  means  of 
defence  are  overcome,  tlie  parasitic  organisms  gain  the  upper  hand  and 
lead  to  death. 

There  is  yet  another  reaction  to  injvirious  intluences  exhibited  by 
the  Protozoa  into  which  it  is  necessary  that  I  sh<»nld  enter  at  some 
length.  This  is  exhibited  by  the  anio'ltii.  but  (^an  be  and  has  been  most 
fully  investigated   in  the   myxomyeetes  —  multicellular   forms   which 


5« 


SYSTEM  OF  MEDICINE 


can  with  equal  propriety  be  classed  as  animals  or  plants,  although 
usually  they  are  included  among  the  latter.  These  organisms  form 
large  plasinodia  (masses  of  protoplasm,  that  is),  in  which,  under  ordi- 
nary conditions,  the  nuclei  are  the  only  indication  of  the  individual 
cells  which  by  their  fusion  have  formed  the  masses.  They  are  to  be 
met  with  in  leaf  mould,  and  on  the  surface  of  moist  decaying  wood  over 
which  they  creep  with  an  amoeboid  movement ;  and  inasmuch  as  they 
may  attain  great  size  —  some  species  attaining  twelve  inches  or  more 
in  length  —  they  form  admirable  material  for  biological  study. 

Ten  years  ago  Stahl,  investigating  one  of  these  myxomycetes  (the 
JEthaliiim  septicuni,  an  organism  found  in  tan  pits),  showed  that  if  placed 
upon  a  moistened  surface  close  to  a  drop  of  infusion  of  oak  bark,  the 
Plasmodium  moved  actively  towards  and  into  the  infusion ;  if  placed 
similarly  near  to  a  solution  of  glucose  (0'5  per  cent)  it  moved  with  equal 
rapidity  away,  and  so  also  in  the  case  of  solutions  of  various  salts.  These 
observations  of  Stahl  were  (if  we  except  Engelmann's  observations  in 
1881  upon  the  tendency  of  sundry  bacteria  to  remove  from  regions  poor 
in  oxygen  to  those  where  oxygen  is  present  in  abundance)  the  first  of  a 
series  of  observations  upon  the  attraction  and  repulsion  of  plants  and 
portions  of  plants  by  chemical  substances.  To  this  property  Pf  effer,  who 
has  made  the  fullest  series  of  studies  upon  it,  has  given  the  name  of 
cheniiotaxis,  in  place  of  Stahl's  narrower  "  trophotropism " ;  and  one 
speaks  of  a  positive  or  a  negfitive  cheniiotaxis  according  to  the  attrac- 
tion or  repulsion  exerted.  If,  as  Metschnikoff  has  pointed  out,  the 
advancing  edge  of  one  of  these  plasmodia  (of  Physarum)  be  injured  by 
cauterisation,  the  region  of  injury  dies ;  the  protoplasmic  currents, 
which  had  been  advancing,  reverse  themselves  abruptly,  and  within  an 
hour  the  plasmodium  has  moved  away,  leaving  the  debris  of  the 
destroyed  region  behind.  These  experiments  are  so  simple,  and  the 
results  obtained  seem  so  natural,  that  it  may  be  asked  whether  it  be 
worth  while  to  attach  a  name  to  this  property  of  living  matter.  Yet  the 
name  is  in  itself  an  aid  to  bearing  these  properties  in  mind;  and,  as  will 
be  pointed  out  later,  the  recognition  of  them  is  of  material  help  in  solving 
certain  of  the  difficulties  that  present  themselves  in  the  study  of  inflam- 
nuitiou  in  the  higher  animals.  Among  tlu'se  myxomycetes  another  fact 
can  be  nuide  out.  Stahl  observed  tluit  the  ])lasniodium  of  Fuligo,  which 
at  hrst  nuwes  away  from  a  two  i)cr  cent  sohition  of  common  salt,  will 
after  a  tinte  (more  esiM'cially  if  it  has  sutt'ered  from  hick  of  water)  adapt 
itself  to  the  sohition,  advancing  its  pseudopodiaor  ))roto])lasmi<'  processes 
into  it.  With  other  myxomycetes  tlie  same  adaptation  has  been  observed. 
That  is  to  say,  by  use  or  adaptation  a  negative  may  be  transformed  into 
a  i)ositive  cheniiotaxis.     To  this  change  I  shall  have  occasion  to  revert. 

The  Response  to  Injury  among  the  Metazoa.  —  Passing  from  the 
Protozoa  to  tlie  iMetazoii,  we  reiich  immediately  (or  almost  immedi- 
ately) a  series  of  beings  in  which  the  division  of  labour  among 
the  ct'lls  has  led  to  the  development  of  three  cell  layers — an  (»nter 
ectoderm,  an  inner  endodurm,  and  an  intermediate  ht.yer  of  mesoderm. 


INFLAMMA  TION 


59 


Even  in  the  very  lowest  forms  among  the  Metazoa  it  is  noticeable 
that  of  these  three  layers  there  is  one,  the  mesoderm,  whose  cells 
have  the  especial  function  of  reacting  when  any  irritant  or  injurious 
stimulation  is  applied  to  the  organism.  Taking  what  are  perhaps  the 
simplest  forms  in  which  to  observe  the  relationship  and  properties  of 
these  layers,  Metschnikoff  has  studied  these  results  of  injury  in  the  larval 
forms  of  astropecten  and  other  echinoderms.  At  one  well-recognisable 
stage  these  larva)  resemble  little  more  than  the  gastrula  stage  of  the 
embry ologist ;  the  endoderm  or  hypoblast  appears  as  a  cul-de-sac  —  an 
invagination  of  the  ectoderm  or  epiblast  —  while  the  mesoderm  is  repre- 
sented by  amoeboid  cells,  budded  oif  from  the  endoderm,  lying  or  float- 
ing in  the  semiliquid  substance  tilling  the  general  body  cavity.  The 
ectoderm  is  so  delicate  that  any  sharp  substance  can  readily  penetrate 
into  the  body  cavity ;  and,  when  this  happens,  it  is  noticeable  that  the 
wandering  mesodermal  cells  make  their  way  to  the  foreign  body,  attach 
themselves  to  it,  and  fuse  into  plasmodial  masses,  thus  forming  a 
wall,  as  it  were,  around  the  invading  substance,  and  cutting  it  off  from 
the  general  body  system.  Here,  then,  in  an  organism  possessing  neither 
nervous  nor  vascular  system,  the  reaction  to  injury,  where  that  injxiry 
has  not  been  sufficiently  intense  to  cause  destruction  of  the  outer  layer 
of  cells,  is  simply  and  solely  confined  to  the  wandering  cells  of  the 
body ;  there  is  no  effusion  of  fluid ;  there  is  not  necessarily  phagocytosis 
on  the  part  of  these  cells ;  any  digestive  and  destructive  action  on  their 
part — any  attempt  in  this  way  to  remove  the  forei^  body — must  then 
be  by  excretion,  hy  extracellular  action.  At  the  same  time,  this  fusion 
of  the  cells  and  formation  of  a  plasmodium  around  foreign  substances  of 
greater  diameter  than  the  individual  mesodermal  cells  may  bo  looked 
upon  as  a  mechanism  whereby  the  equivalent  of  intracellular  digestion 
is  gained.  But,  as  among  these  low  forms  cases  occur  in  which,  without 
the  formation  of  plasmodia,  the  cells  perform  their  destructive  action 
upon  bodies  of  larger  size  than  themselves  we  do  not  lack  examples  of 
what  must  be  considered  as  excretory  destructive  powers  on  their  part. 
That  these  cells  in  the  echinoderms  are  also  capable  of  destroying  minute 
foreign  bodies  by  intracellular  action,  that  is,  by  phagocytosis,  lias  been 
denumstrated  in  the  larger  transi)arent  larval  form  known  as  Uipinnaria 
Asterigera;  on  introducing  l)acteria  under  its  ectoderm  the  nu'sodermal 
cells  are  seen  to  api)roach,  and  by  their  long  i)seudopodia  to  adhere  to 
and  ingest  the  still  living  motile  bacteria,  whicli  are  rapidly  digested. 

liesides  this  reaction  to  injury  on  the  part  of  the  mesodermal  cells, 
a  further  response  is  exhibited  to  a  remarkable  degree  among  the 
lower  Metazoa —  I  refer  to  the  great  i)ower  of  regeneration  of  lost  i)arts, 
of  cell  lu'oliferation  leading  to  the  re])rodu(^tion  of  destroyed  regituis. 
This  ])0wer  is  l)est  seen  in  the  classical  example  of  the  Hydra,  which 
may  be  cut  into  many  pieces,  each  one  of  which  is  cai)able  of 
glowing,  so  that  in  a  relatively  short  tinn^  it  becomes  a  fully  formed 
individual.  It  is  interesting  to  note  in  rcliition  to  tlie  frecpient  ten- 
dem-y  towards  hyperpliusia  and  excess  growth  following  upon  injury  in 


6o 


S  VS '     :if  OF  MEDICINE 


h 


the  higher  animals,  that  iiiiong  low  forms,  such  as  Hydra  and  Ceri- 
anthus,  the  same  tendency  is  yet  more  strongly  marked.  Thus,  as 
Loeb  points  out,  if  an  incision  be  made  in  the  stem  of  a  Hydra,  a 
whole  new  oral  pole,  provided  with  tentacles,  will  branch  out  from  the 
region  of  cell  destruction.  In  the  actinian  Cerianthus  the  process  is 
not  quite  so  extensive ;  yet  from  the  lower  lip  of  the  lateral  incision  a 
set  of  tentacles  develops  in  all  respects  similar  to  those  around  the 
mouth. 

Ascending  to  the  Worms,  we  find  that  the  protective  agency  devolves 
upon  mesodermal  cells  suspended  in  the  perivisceral  fluid,  and  again 
forming  the  peritoneal  endothelium.  We  arrive,  that  is  to  say,  at  a 
state  in  which  a  lymphatic  system  may  be  said  to  be  present ;  for  the 
spaces  in  which  the  free  corpuscles  lie  are  strictly  homologous  to  the 
lymph-containing  spaces  of  the  vertebrate  organism,  and  these  corpuscles 
may  be  regarded  as  lymph  corpuscles ;  the  peritoneal  endothelium  cor- 
responds with  the  mesodermal  peritoneal  endothelium  of  vertebrata. 

Among  the  annelids  the  process  of  reaction  to  injury  may  be  well 
followed  in  the  earth  worm  by  studying  the  sequence  of  changes  that 
occur  around  the  gregarines  which  infest  the  male  genital  organs. 
While  these  parasites  are  active  by  their  movements  they  prevent  the 
adhesion  of  the  wandering  cells;  but  so  soon  as  they  pass  into  the 
resting  stage  antecedent  to  spore  formation,  the  cells  form  a  thick  mass 
around  them.  The  parasite  on  its  part  forms  a  thick  cyst  wall ;  never- 
theless, it  may  not  unf  requently  be  observed  that,  despite  this  protection, 
the  parasite  changes  its  appearance  under  the  action  of  the  surround- 
ing i)lasmodium,  and  in  fact  is  killed.  While  this  is  happening  no  change 
could  be  detected  by  Metschnikoff  in  the  neighbouring  blood-vessels ; 
these  appear  to  remain  completely  inactive :  no  exudation  is  noticeable 
nor  any  recognisable  change  in  volume. 

While  among  the  Worms  a  well-developed  and  closed  vascular 
system  is  not  unfrequently  present,  in  other  animal  forms,  which  in 
most  respects  present  a  much  more  complex  and  advanced  develop- 
ment, namely,  in  the  Arthropods  and  Tunicates,  this  is  not  the  case. 
In  these  the  blood  pours  from  tlie  tubular  heart  sooner  or  later  into  the 
liic'iuue  of  the  general  body  cavity ;  and  whether  veins  be  absent  (as 
is  most  usual),  or  present  (as  in  the  Cephalopods),  the  blood  is  sucked 
back  from  the  body  (Uivity  into  the  heart.  Tliis  incomplete  circulation, 
interesting  as  it  is  in  connection  with  the  development  of  the  vertebrate 
circulation,  is  interesting  also  from  the  fiu^t  that  its  incompleteness 
in  these  large  and  wide-si)read  classes  )f  animals  prevents  reaction  to 
injury  from  being  associated  with  vascu  ar  changes.  TIh^  blood  in  these 
animals,  circulating  through  the  ramilications  of  the  body  cavity,  is 
evidently  a  mesodermal  fluid,  if  it  may  l)o  so  termed.  Its  corpuscles 
are  clearly  mesodermal;  and  without  going  into  lull  details  as  to  the 
properties  of  tliese  (M)rpuscles,  it  may  be  said  that  tliey  rc^present  an 
liitiM-esting  series  of  stages  in  the  subdivision  of  laliour,  Kor  exam|»le, 
■is  Mr.  Hardy  has  shown  us  in  a  low  form  of  crustacean  like  Uaphuia  ;the 


INFLAMMA  TION 


6l 


water  flea),  but  one  form  of  cell  is  present,  whereas  in  the  highly- 
developed  Astacus  (the  cray  fish),  there  are  three  distinct  forms  of 
leucocytes  (no  red  corpuscles  being  present),  each  of  which  appears 
to  have  distinct  functions.  The  one  form  in  Daphnia  has  the  property 
of  taking  up  fat  globules  and  food  particles  from  the  alimentary 
tract,  foreign  particles,  such  as  granules  of  carmine  or  Indian  ink,  and 
the  spores  of  parasites  (Monospora,  Metschnikoff) ;  it  is  granulated,  con- 
taining minute  spherules  which  stain  with  basic  aniline  dyes  (basophils 
granules),  and  under  certain  circumstances  it  may  be  seen  to  explode 
with  lightning-like  rapidity.  In  the  higher  Astacus  there  are  in  the 
circulating  haemal  fluid  two  varieties  of  cells:  one  is  extraordinarily 
explosive ;  when  removed  from  the  body  cavity  it  gives  off  fine  blebs 
or  vesicles  of  its  substance  with  such  rapidity  that,  unless  the  greatest 
care  be  taken,  nothing  is  seen  of  the  cell  save  its  nucleus ;  this  form  is 
phagocytic :  the  other  form  is  far  more  stable,  and  is  loaded  with  large 
spherules  which  have  a  great  affinity  for  acid  dyes  —  they  are  eosino- 
philous  —  may  be  actively  extruded,  and  undergo  decomposition ;  these 
cells  never  act  as  phagocytes.  The  third  form,  with  basophile  granules, 
is  rarely  found  in  the  blood,  and  then  only  as  the  result  of  special 
stimuli ;  but  it  is  present  in  considerable  numbers  in  the  peculiar  tissue 
which  forms  a  sheath  around  certain  of  the  arteries  —  Haeckel's  "  Zell- 
gewebe ;  "  this  form  is  phagocytic,  and  can  be  seen  to  contain  globules 
of  ingested  fat. 

As  Metschnikoff  demonstrated,  in  his  most  remarkable  study  upon 
a  disease  of  Daphnia  caused  by  the  entry  of  the  spores  of  a  yeastlike 
organism  (the  Monosiwra)  into  its  body  cavity,  its  one  form  of  leuco- 
cyte can  be  seen  to  react  swiftly  towards  the  spores;  the  cells  ap- 
proach them,  form  a  plasmodium  around  and  eventually  digest  and 
destroy  them.  If,  on  the  other  hand,  in  consequence  of  their  great 
numbers  or  the  relative  paucity  of  the  leucocytes,  certain  of  the  spores 
be  not  attacked  and  develop  uninterruptedly  into  mature  torulaj,  the 
leucocytos  show  no  tendency  to  approach  them  —  in  fact,  their  neigh- 
bourhood leads  to  the  explosion  of  the  leucocytes  —  and  the  torulie, 
multiplying,  }ead  to  the  death  of  the  organism.  Often,  again,  brown 
eschars  may  be  recogni^tid  ujwn  the  transparent  carapace  of  a  Daphnia, 
due  to  injuries  by  other  individuals;  beneath  these  scars  are  to  be  found 
masses  of  leucocytes  whicli  remain  in  the  region  of  injury  until  the  cells 
of  the  tissue  have  ])roliferated,  and  there  is  complete  union  and  repair. 

In  addition,  then,  to  the  immediate  reparative  and  protetitive  re- 
action ot  the  leucocytes,  there  is  exhibited  among  the  higher  invertebrata 
a  later  reaction  in  the  shape  of  proliferation  of  the  fixed  cells.  This 
proliferation,  while  not  so  extensive  as  among  the  lower  invertebrates, 
can  nevertheless  be  very  great;  and  cells  of  all  forms,  whetlier  of  hypo-, 
meso-  or  epiblastic  origin,  and  tissues  so  highly  developed  as  the  muscular 
and  nervous,  may  participate  in  it.  In  illustration  of  tlie  ample  power 
of  tissue  reproduction  after  injury  possj'sscd  by  these  animals,  I  need  but 
mention  the  trite  examples  of  the  reproduction  of  the  hinder  segments 


6t 


62 


SYSTEM  OF  MEDICINE 


of  divided  worms,  and  in  crustaceans  the  restoration  of  injured  and  cast 
off  claws  and  appendages. 

Many  more  instances  might  be  given  to  show  that  the  reaction  to 
injury  remains  essentially  a  reaction  on  the  part  of  the  wandering  and 
fixed  mesoblastic  cells  of  the  organism,  followed  in  sundry  cases  by 
proliferation  of  the  fixed  epi-,  meso-  and  hypoblastic  cells,  and  by  repair 
where  these  have  been  destroyed.  Although  these  arthropods,  molluscs 
and  tunicates  have  a  vascular  system,  yet,  inasmuch  as  this  is  open,  its 
changes,  if  they  occur,  could  scarcely  modify  the  inflammatory  process. 

The  Response  to  Injury  among  the  Vertebrata.  —  If  now  we  pass  to 
the  vertebrates,  the  picture  presented  is  far  more  complex :  not  only  do 
these  present  a  highly-developed  nervous  system,  but,  moreover,  the 
blood  is  enclosed  in  a  complete  vascular  system.  We  shall  now  consider 
at  length  the  results  of  an  injury  of  an  organ  in  one  of  these  higher 
animals. 


Chapter  3.  —  The  Main  Forms  op  the  Process  op  Acute  Inplam- 

MATION    IN   the   HiOHER   AnIMALS 

The  Experimental  Production  of  Inflammation  in  Non-Vascular  Areas. 

—  Let  us  begin  with  the  succession  of  changes  that  occurs  in  the  sim- 
plest case,  namely,  in  a  non-vascular  area,  in  one  of  the  lowest  vertebrate 
forms  —  for  instance,  in  the  embryonic  axolotl  ten  to  fifteen  days  old; 
let  us  curarise  it,  and  apply  a  minute  crystal  of  silver  nitrate  to  the 
side  of  its  flattened  transparent  tail  fin,  washing  away  the  remains  of 
the  crystal  with  salt  solution;  or  again,  we  may  pass  into  the  tail  a 
small  needle  filled  with  finely-powdered  carmine.  l>y  either  procedure 
a  certain  number  of  cells  is  destroyed.  The  neighbourhood  of  tlie 
injury  now  becomes  swollen  (it  may  bu  l)y  imbibition  of  water  through 
the  wound),  and  the  surrounding  cells  tumefied,  vacuolated  and  less 
refractile.  This  is  the^ns^  starje — that  of  injury  and  modification  of  the 
surrounding  tissue.  In  a  little  time  a  few  wandering  cells  (leucocytos) 
approach  the  injured  region;  by  the  next  day  these  are  present  in 
fair  numbers,  and  can  be  seen  to  have  taken  up  the  particles  of  carmine 
or  debris  of  the  destroyed  tissue.  This  is  the  second  stage  —  that  of 
immigration  of  leucocytes.  There  are  no  vessels  in  the  transparent 
fin  of  these  young  axolotls,  no  dilation  of  those  nearest  to  the  fin, 
and  no  diapedesis.  All  the  leucocytes  that  pass  to  the  part  are  pre- 
existing wandering  cells  of  the  connective  tissue, — a  fact  of  some  little 
importance  in  connection  with  the  origin  of  certain  of  the  pus  cells  in  the 
suppurative  process  of  higher  animals.  The  third  stage  is  that  of  repair, 
of  prolif(>ration  of  tlie  injured  epithelium,  return  of  the  fixed  cells  of 
tlie  tissue  to  their  jjrevious  state,  and  emigration  of  the  wandering  cells. 
A  very  similar  jjrogress  of  events  occurs  if  the  experiment  be  re|)eated 
upon  the  tail  fin  of  the  yovuig  newt.  Tlic^  same  rapid  alteration  in  the 
large  branched  connective  tissiu'  cells  (wliich  become  vacuolated  as  their 


INFLAMMA  TION 


6S 


Ions  processes  are  drawn  in  and  shortened),  and  the  same  immigration 
of  motile  cells  from  the  surrounding  connective  tissue  are  to  be  seen ; 
biit  here  we  now  find  the  earliest  evidence  of  vascular  participation,  for, 
according  to  Metschnikoff,  complete  arrest  of  the  circixlation  may  occur 
in  the  nearest  vascular  loop,  liy  the  next  day  the  parts  have  returned 
to  the  normal  condition. 

If  from  these  cases  wo  pass  to  mild  inflammatory  disturbances 
affecting  the  non-vascular  regions  of  animals  far  higher  in  the  scale,  wo 
again  discover  a  like  process  of  events.  For  this  purpose  the.  cornea 
affords  an  excellent  ojjportunity ;  in  health  it  is  absolutely  non-vascular ; 
it  is  perfectly  transparent,  and  is  so  thin  that  it  can  readily  be  examined 
microscopically. 

The  cornea  of  mammalia,  and  indeed  of  vertebrates  in  general,  is 
formed  of  fibres  which  run  in  layers  parallel  to  the  surface.  These 
fibres,  while  roughly  arranged  side  by  side  and  parallel  to  one  another 
in  any  given  layer,  are  placed  at  an  angle  to  the  fibres  of  the  layers 
above  and  below.  Although  free  from  blood-vessels  the  cornea  is 
far  from  being  devoid  of  channels  along  which  lymph  freely  passes. 
Between  the  several  layers  there  exist  spaces  in  which  lie  the  flattened 
connective  tissue  cells  of  the  organ ;  and,  by  means  of  numerous  fine 
channels,  these  spaces  around  the  cells  are  connected  with  similar 
spaces  lying  anteriorly,  posteriorly  and  laterally.  Through  this  rich 
anastomosis  of  channels  there  is  a  free  flow  of  lymph.  These  channels 
arc  really  continuations  of  the  body  cavity  of  the  animal ;  they  repre- 
sent, and  in  fact  play  the  same  part  as  the  single  body  cavity  of  such  a 
simple  form  as  the  larva  of  Astropecten,  while  the  cells  lying  in  the 
spaces  are  mesoblastic  cells  which  have  become  fixed. 

Few  studies  are  better  calculated  to  impress  the  ir  .stigator  with  a 
sense  of  the  depth  of  the  well  at  the  bottom  of  which  truth  lies,  than  a 
research  into  the  abundant  literature  dealing  with  observations  upon  the 
stages  of  the  inflammatory  process  as  it  occurs  in  the  cornea,  and  with 
the  deductions  therefrom.  One  after  another  the  adherents  to  succes- 
sive forms  of  inflanuuatory  belief  have  found  in  experiments  upon  this 
simple  tissue  ample  support  for  their  particular  creeds. 

Selecting  from  among  the  many  observations  those  which  have  stood 
the  test  of  time,  I  will  begin  with  the  simplest,  and  pass  on  to  those 
dealing  with  an  increasing  intensity  of  the  inflammatory  process. 

If,  as  Senftlobon  first  pointed  out,  the  centre  of  the  corniM  of  a 
rabbit  bo  washed  with  a  strong  solution  of  zinc  chloride,  then,  in  favour- 
alile  cases,  although  the  epithelial  covering  be  gravely  injured,  there  may 
bo  no  actual  rui)ture  of  the  outer  layers  of  the  tissue.  Such  a  cornea 
ienu)ved  twenty-four  hours  later  may  show  no  sign  of  migration  of 
leucocytes  —  no  sign,  again,  of  congestion  of  the  vessels  at  the  peri- 
])hi'ry.  The  only  indications  of  injury  and  reaction  may  be  the  destruc- 
tion of  the  corneal  corpuscles  immediately  beneath  the  cauterised  area, 
and  the  apivarance  of  a  zone  surrounding  this  in  which  the  corneal 
corpuscles  appear  enlarged,  tlistinct  and  tunu^lied.     The  ])rocess  may 


64 


SYSTEM  OF  MEDICINE 


continue  and  advance  insensibly  to  repair  without  the  intervention  of 
leucocytes ;  the  hypertrophying  cells  of  the  "  granular  "  zone  eventually 
undergoing  karyokinesis,  and  thus  by  multiplication  replacing  the  cor- 
puscles destroyed. 

Here,  then,  necrosis  and  new  growth  of  the  fixed  cells  of  the  tissue 
are  the  only  recognisable  factors  in  the  process  of  repair  of  injury.  It 
must  be  confessed  that  the  conditions  permitting  this  simplest  form  of 
reaction  are  of  rare  occurrence ;  it  is  worthy  of  attention  that  they  can 
exist. 

By  a  slight  modification  of  the  preceding  conditions  another  factor 
may  be  brought  into  play.  If,  after  cauterisation  in  the  manner  above 
described,  a  break  be  made  into  the  cauterised  surface;  or  if  again, 
without  cauterisation,  a  little  of  the  corneal  tissue  bo  removed,  then  in 
a  few  hours  a  small  whitish  opacity  is  to  be  noticed  within  the  corneal 
tissue  in  the  immediate  neighbourhood  of  the  break  in  the  continuity,  and 
upon  examination  this  opacity  is  found  to  be  due  to  a  massing  of  small 
round  cells.  As  there  is  at  this  moment  no  sign  of  proliferation  of  the 
connective  tissue  cells  of  the  cornea,  these  newly-collected  cells  can  only 
be  leucocytes ;  and  further  examination  of  their  properties  proves  them 
to  be  such :  there  is,  however,  no  evidence  of  dilation  of  the  peripheral 
vessels,  no  indication  of  diapedesis  through  their  walls.  The  leucocytes, 
therefore,  can  only  have  entered  into  the  wound  from  the  cornea  itself 
and  from  the  conjunctiva  and  the  lachrymal  fluid  bathing  it.  In  this 
experiment  the  inflammatory  process  is  represented  by  destruction  of 
tissue  and  immigration  of  leucocytes,  followed  by  repair ;  neither  the 
vascular  nor  the  nervous  system  play  any  part  in  it.  We  are  forced  to 
the  conclusion  that  the  leucocytes  have  massed  themselves  in  the 
injured  area  purely  on  their  own  initiative ;  and  that  there  must  be  an 
attraction,  a  chemiotaxis  or  chemiotropism,  leading  them  actively  to 
approach  the  region  of  cell  destruction. 

The  observations  made  upon  these  two  simple  cases  help  us  materi- 
ally to  understand  the  series  of  events  which  occur  in  more  intense 
inflammation  of  the  cornea,  such  as  that  produced  by  injuring  the  surface 
and  causing  the  entrance  into  the  injured  region  of  a  small  quantity 
of  a  pure  culture  of  the  Pyococcus  aureus.  This  may  be  accomplished 
by  injecting  the  culture  into  the  centre  of  the  healthy  cornea  by  means 
of  the  needle  of  a  Pravaz  syringe  (Jacobs).  The  micrococci  so  intro- 
duced grow  rapidly,  the  growth  so  extending  along  the  lymph  spaces 
that  a  branched  mass  of  the  microbes  is  produced,  having  the  spot  of 
inoculation  as  centre.  Around  the  growth  as  it  extends  may  bo  seen 
a  sharply-marked  area  in  which  the  corneal  corpuscles  show  evidences 
of  degeneration ;  the  nuclei  stain  faintly,  and  the  corpuscles,  speaking 
generally,  have  a  shrunken  appearance.  Here,  again,  the  first  effect  of 
a  microbic,  as  of  a  simple  chemical  injury,  is  to  bring  about  degeneration 
of  the  fixed  cells  of  the  tissue.  Within  eighteen  hours  the  zone  of  pro- 
liferating cocci  and  cell  degeneration  is  well  marked;  and  now  the 
second  stage  begins  to  bo  clearly  manifest,  namely,  the  determination 


INFLAMMATION 


6S 


of  leucocytes  to  the  seat  of  injury.  Within  twenty-four  hours  there 
is  a  dense  packing  of  these  corpuscles  around  the  central  degenerated 
area,  and  great  nmnbers  of  leucocytes  may  be  seen  converging  along  the 
lymph  spaces  from  the  periphery  of  the  cornea.  This  is  the  second  stage 
of  the  process,  the  first  stage  of  reaction  to  the  injury  inflicted  by  the 
invading  micro-organisms.  If,  as  by  Cohnheim '  in  his  original  experi- 
ments upon  the  injury  to  the  cornea,  more  careful  examination  be  made 
into  the  stages  of  the  determination  of  leucocytes,  it  can  be  seen  that  this 
determination  is  closely  related  to  changes  set  up  in  the  vessels  at  the 
periphery  of  the  cornea;  they  become  more  prominent,  the  region  has  a 
congested  appearance,  the  smaller  as  well  as  the  larger  vessels  are 
dilated,  and  there  is  abundant  evidence  that  the  leucocytes  are  passing 
out  from  the  contained  blood  into  the  surrounding  lymph  spaces.  In- 
deed the  accumulation  of  leucocytes  shows  itself  first  at  the  periphery  of 
the  cornea  near  the  vessels,  and  gradually  approaches  the  region  of 
injury.  Into  the  mechanism  of  this  diapedesis,  and  into  a  fuller  descrip- 
tion of  the  changes  that  take  place  in  the  blood-current  in  these  distended 
vessels,  I  shall  enter  later  when  discussing  the  changes  in  highly  vascular 
regions.  Suffice  it  to  say  here  that  no  distinction  can  be  made  out  between 
the  behaviour  of  the  leucocytes  in  the  previous  experiment,  when  they 
entered  the  wounded  area  from  the  external  surface,  and  in  this  where 
the  majority)  find  their  entrance  from  the  blood;  as  in  the  previous  case 
the  part  played  was  evidently  active,  so  must  it  be  here  also.  We  cannot 
arrive  at  any  other  conclusion  than  that  some  attractive  force  leads  to 
their  determination  towards  the  inflammatory  focus.  As  we  can  easily 
show,  by  repeating  the  experiment,  many  of  these  leucocytes  take  up  and 
contain  numerous  cocci,  while  other  cocci  remain  free  in  the  tissue 
spaces.  Many  of  the  leucocytes  degenerate  and  present  a  broken  down 
appearance ;  and,  as  at  the  same  time  an  increasing  area  of  the  corneal 
tissue  becomes  disintegrated,  an  ulcer  appears.  According  to  the  viru- 
lence of  the  culture  and  the  reaction  on  the  part  of  the  organism,  the 
process  may  now  extend,  a  larger  and  larger  portion  of  the  corneal 
tissue  becoming  affected ;  or,  on  the  other  hand,  there  may  be  an  arrest 
of  the  progress,  the  massing  of  the  leucocytes  preventing,  as  a  barrier, 
the  further  extension  of  the  micrococci  into  the  lymph  spaces ;  '^  while 
at  the  same  time  there  is  an  advance  of  newly-formed  capillary  vessels 
into  the  previously  non-vascular  tissue.  It  is  to  be  noticed  that  the 
blood-vessels  at  the  periphery  of  the  cornea  are  prominent  and  dilated, 
and  from  them  fine  new  vessels  with  very  delicate  walls  pass  towards 
tlie  injured  region.  At  the  same  time  many  of  the  corneal  corpuscles, 
outside  the  area  of  destruction,  can  by  appropriate  staining  be  seen 
undergoing  mitosis  and  proliferating.  Thus  the  active  repair  of  the 
tissue  is  initiated. 


]' 


( 


1  There  can  bo  no  qiie.stion  that  Cohnheim  In  his  experiments  induced  not  a  simple 
keratitis  but  one  which  in  tlie  absence  of  aseptic  precautions  rapidly  became  septic  and 
suppurijtive. 

i<  Into  tbo  details  of  this  action  I  shall  enter  moro  fully  later. 


VOL.   I 


F 


«5 

ours  there 

^generated 

J  along  the 

cond  stage 

sed  by  the 

lal  expei'i- 

n  be  made 

n  that  this 

jels  at  the 

igion  has  a 

essels  are 

,re  passing 

Daces.     In- 

jriphery  of 

region  of 

er  descrip- 

5  distended 

ly  vascular 

ut  between 

when  they 

this  where 

Bvious  case 

We  cannot 

ee  leads  to 

can  easily 

ake  up  and 

the  tissue 

oken  down 

le  corneal 

the  viru- 

anism,  the 

le  corneal 

B  an  arrest 

a  barrier, 

es ;  ^  while 

iry  vessels 

1  that  the 

id  dilated, 

s  towards 

orpuscles, 

g  be  seen 

air  of  the 


lot  a  simple 
10  soptic  niid 


66 


SYSTEM  OF  MEDICINE 


{ 


The  Experimental  Production  of  Inflammation  in  Vascular  Areas. — 

From  this  study  of  inflammation,  as  it  occurs  in  a  region  devoid  of 
blood-vessels,  let  us  now  pass  on  to  the  more  complicated  process  of 
inflammation  in  vascular  areas ;  and,  as  in  the  previous  case  we  considered 
an  ascending  or  advancing  series  of  reactive  changes,  so  here  let  us  begin 
with  the  slightest  injury  associated  with  the  mildest  reaction,  and  pass 
onwards  to  states  in  which  the  inflammatory  manifestations  are  more 
and  more  pronounced. 

If  an  incision  be  made  with  a  perfectly  aseptic  instrument  into  the 
skin,  also  rendered  aseptic,  and  be  so  made  as  to  divide  the  dermis 
and  tissues  immediately  below,  without  at  the  same  time  injuring  any 
large  vessel,  it  is  the  common  experience  of  modern  surgeons  that 
repair  takes  place  with  the  minimal  amount  of  change  recognisable  as 
inflammatory.  Repair  takes  place  indeed  so  rapidly  that,  if  the 
divided  structures  have  come  or  have  been  brought  into  immediate 
contact,  there  may  be  firm  adhesion  at  the  end  of  twenty-four  hours. 
This  is  primary  union,  or  union  by  first  intention,  which,  rare  in  the 
old  days,  commonly  occurs  in  this  era  of  aseptic  surgery.  The  full 
sequence  of  events  in  these  cases  cannot,  it  is  true,  be  well  determined 
by  continuous  microscopic  examination;  but  if  the  rabbit  or  dog  be 
employed,  and  tissues,  wounded  in  the  manner  described,  be  removed 
and  examined  at  successive  short  intervals,  we  see  that  the  changes 
which  occur  are  mainly,  nay  almost  entirely,  related  to  the  pre-existing 
cells  of  the  part.  The  section  divides  a  certain  number  of  capillaries ; 
but  in  the  very  act  of  division  the  divided  walls  are  apparently  brought 
together ;  and,  partly  by  this  means,  partly  by  contraction,  the  lumina  of 
these  minute  vessels  become  occluded,  and  the  haemorrhage  into  the 
wound  is  altogether  inconsiderable.  Within  an  hour  after  the  operation 
it  is  evident  to  the  naked  eye  of  a  careful  examiner  that  the  immediate 
neighbourhood  of  the  wound  is  slightly  reddened  and  tumefied,  but 
only  very  slightly ;  and,  associated  with  this,  there  is  a  feeble  exudation 
between  the  apposed  surfaces.  But  the  exudation  is  not  great,  and 
even  within  this  first  hour  after  the  infliction  of  the  wound  there  may  be 
development  of  fibrin  and  coagulation  of  the  exudate,  leading  to  the 
formation  of  a  provisional  cementing  together  of  the  opposed  surfaces. 
In  this  exudation,  and  in  the  tissues  in  the  immediate  neighbourhood, 
the  leucocytes  that  have  undergone  diapedesis  may  be  few  and  far 
between,  and  may  scarcely  attract  attention.  The  reaction,  then,  on  the 
part  of  the  vessels  and  of  the  leucocytes  is  of  the  slightest.  Study  of 
sections  shows  that  the  main  role  is  played  by  tlic  pre-existing  cells  of 
the  part ;  of  these  a  certain  number  (not  so  many  as  might  d  priori  be 
expected)  are  destroyed  immediately,  and  show  all  the  signs  of  disinte- 
gration ;  a  number  relatively  large  have  been  injured  only,  their  nuclei 
remaining  intact,  though  their  processes  or  some  portions  of  the  cell 
bodies  have  been  cut  through.  It  is  ditticult  to  determine  these 
injuries  in  the  small  cells  of  the  cutaneous  tissues ;  they  are  better  seen 
in  the  peritoneum  when  slight  inflammatory  changes  have  there  been 


F 


INFLAMMATION 


67 


induced.  This,  however,  can  be  made  out  that  the  cells  in  the  immedi- 
ate neighbourhood  of  the  wound  became  enlarged,  and,  without  showing 
signs  of  division,  prolong  themselves  (that  is  to  say,  send  out  prolonga- 
tions) into  the  region  of  the  provisional  fibrinous  cicatrix.  In  this  way, 
before  the  end  of  the  second  day,  there  may  be  a  more  or  less  complete 
replacement  of  the  primary  unorganised  cementing  substance  by  organ- 
ised growing  tissue,  —  formed,  in  the  first  place,  by  the  interlacing  of 
processes  from  the  neighbouring  cells ;  in  the  second,  and  later,  by  a 
multiplication  of  these  cells,  together  with  a  development  of  new 
capillaries,  few  in  number,  which  branch  off  from  the  slightly-congested 
vessels  in  the  neighbourhood.  Thus  in  this  case  the  process  of  repair 
is  characteristically  associated  with  hypertrophy  and  the  new  growth 
of  the  fixed  cells  of  the  tissue ;  while  vascular  changes,  exudation  and 
leucocytosis,  are  relatively  little  marked.  I  have,  however,  never  come 
across  a  case  in  which  they  have  been  entirely  absent,  save  when  the 
section  has  been  truly  extra-vascular — that  is  to  say,  when  it  has  not 
penetrated  into  the  vascular  region  of  the  skin,  and  has  aCEected  only 
the  epidermis  and  outermost  layers  of  the  dermis.  In  such  cases  the 
response  to  injury  may  show  itself  purely  as  a  proliferation  of  the 
epithelial  cells. 

As  I  have  said,  observations  of  the  above  nature  labour  under  the 
disadvantage  that  they  must  of  necessity  be  discontinuous.  I  bring 
them  in  at  this  point,  inasmuch  as  they  represent  the  mildest  condition 
of  the  inflammatory  reaction.  I  have  not  personally  observed  this 
series  of  changes  in  tissues  which  permit  of  continued  study  under 
aseptic  conditions;  neither  am  I  acquainted  with  any  observations 
wholly  fulfilling  these  conditions — made,  that  is  to  say,  upon  trans- 
parent vascular  tissues  subjected  to  the  mildest  aseptic  injury  and 
examined  continuously  under  the  microscope. 

The  response  to  injury  in  the  cases  just  mentioned  was  of  the 
slightest.  Let  me  now  pass  on  to  cases  in  which  it  becomes  more  pro- 
nounced; and  in  order  to  continue  the  comparative  study  of  inflam- 
mation I  would  first  describe  the  series  of  enenU  in  a  highly  vaseidar 
and  transparent  region  in  a  low  vertebrate  animal,  namely,  in  the 
tadpole's  tail.  If  this  be  injured,  either  by  the  application  of  a  caustic 
or  by  the  introduction  of  a  foreign  inert  body  into  its  substance,  a 
definite  advance  upon  what  was  recognisable  in  the  case  of  the  axolotl, 
for  example,  is  to  be  made  out.  Here  the  tail  is  very  vascular,  the 
wandering  cells  of  the  connective  tissue  are  very  few  in  number,  while 
the  blood  is  fairly  rich  in  leucocytes  which  are  small  relatively  to  the 
size  of  the  vessels.  The  results  of  injury  are  a  congestion  of  the 
vessels,  noticeable  within  fifteen  minutes,  and  a  well-marked  determi- 
nation of  leucocytes  to  the  injured  region.  These  cells,  in  the  main, 
pass  out  from  the  vessels ;  the  few  leucocytes  pre-existing  in  the  tissue 
appear  to  play  a  very  small  part.  Compared  with  the  axolotl  experiment 
this  observation  is  of  considerable  interest.  Instead  of  a  slight  reaction 
slowly  developing  there  is  a  rapid  reaction ;  instead  of  a  slight  accumula- 


68 


SYSTEM  OF  MEDICINE 


a 


LOn 
ila- 


tion  of  leucocytes  theiv  is  a  most  pronounced  accumulation.  If  there  be 
any  meaning  in  the  determination  of  leucocytes  to  the  region  of  injury, 
then  evidently  the  active  participation  of  the  vessels  of  that  region  in 
the  reactive  process  is  fraught  with  benefit  —  it  is  a  further  important 
factor  developed  with  the  development  and  advance  of  the  organism. 

The  fuller  details  of  this  vascular  interference  in  the  inflammatory 
process  have  been  followed  by  many  observers,  among  whom  first  and 
foremost  was  Cohnheim ;  and  to  this  end  the  frog  has  supplied  the  most 
convenient  means  in  regions  at  once  vascular  and  fairly  transparent, 
such  as  the  web  of  the  hind  feet,  the  tongue,  and  the  mesentery.  Other 
observers  passing  higher  in  the  scale  of  vertebrates  have  employed  the 
mesentery  of  the  cat,  dog,  and  other  mammalia.  Suffice  it  to  say  that, 
with  slight  modifications  due  to  local  conditions  in  the  tissue  examined 
rather  than  to  the  animal  selected,  the  process  has  been  found  to 
present  the  same  features  throughout  the  whole  of  the  adult  vertebrata, 
from  the  reptilia  upwards.  For  general  examination,  perhaps,  the  best 
and  simplest  method  of  observing  the  succession  of  changes  that  follow 
injury  of  a  vascular  area  is  to  be  found  in  what  I  believe  to  be  Coats' 
modification  of  Cohnheim's  original  experiment  upon  the  frog's  web 
(Coats'  Pathology,  1889,  p.  119).  In  order  to  reproduce  as  nearly  as 
possible  the  conditions  of  an  ordinary  wound,  instead  of  employing  a 
caustic  or  chemical  irritant,  a  small  portion  of  the  cutaneous  surface  is 
nipped  off — the  section  being  just  deep  enough  to  pass  through  the 
cutaneous  layers  without  causing  haemorrhage.  For  the  experiment  to 
proceed  satisfactorily,  it  is  necessary  that  the  frog  be  curarised  after 
having  been  pithed.  The  web  of  a  small  frog  is  so  thin  that  the 
changes  occurring  in  and  around  the  vessels  of  the  part  can  readily  be 
followed  even  with  a  high  power  of  the  microscope. 

The  first  change  noticeable  in  the  immediate  neighbourhood  of  the  in- 
jured membrane  is  a  dilation  of  the  vessels,  first  of  the  arteries  and  then  of 
the  veins ;  and  in  this  first  phase  there  is  a  very  evident  acceleration  of 
the  blood  flow.  At  this  early  period  the  capillaries  show  little  evidence 
of  dilation,  but  in  the  course  of  an  hour  expansion  is  readily  distinguish- 
able, and  sundry  capillary  channels,  previously  invisible,  become  occupied 
by  blood  and  show  themselves.  This  first  stage  lasts  for  an  hour,  or  in 
some  cases  perhaps  two,  and  is  followed  by  a  phase  of  slowing  of  the 
blood  current.  While  previously  a  well-marked  axial  stream  of  cor- 
puscles had  been  evident,  with  a  peripheral  zone  of  plasma  devoid  of 
corpuscles,  the  former  now  broadens  out,  the  latter  becomes  less  and 
less,  and  as  it  narrows  an  increasing  number  of  the  clearer  rounded 
haemal  leucocytes  are  to  be  seen  in  it  travelling  at  a  slower  rate  than 
the  more  axial  stream,  and  every  now  and  then  stopping  beside  the 
walls  of  the  vessels,  and  after  a  short  stoppage  passing  on  again.  The 
leucocytes  conduct  themselves  as  if  they  have  become  "  sticky."  * 

As  the  current  becomes  yet  slower  all  distinction  between  axial  and 

1  Even  so  low  down  in  the  scale  as  Daphiiia  this  same  peculiarity  is  noticeable:  there  in 
health,  as  Hardy  has  pointed  out,  the  leucocytes  move  freely ;  but,  if  the  slijjhtest  injury  be 


I  NFL  AM  MA  TION 


69 


peripheral  streams  is  lost ;  the  corpuscles,  closely  packed  together,  fill  the 
whole  lumen ;  the  leucocytes  in  increasing  number  approach  the  vessel 
walls ;  they  adhere  more  firmly,  and  so  long  as  a  current  is  recognisable 
the  action  of  the  stream  leads  them  to  assume  a  pear-shaped  appearance, 
the  rounded  ends  pointing  in  the  direction  of  the  current. 

As  the  stream  slows  gradually  the  corpuscles  may  move  at  last  in  a 
series  of  jerks  synchronous  with  the  heart  beats ;  or  frequently  in  the 
veins  and  capillaries  the  mass  of  blood  may  be  seen  moving  slowly  first 
in  one  direction,  then  in  the  other.  Frequently  one  or  other  of  these 
stages  is  followed  by  complete  stagnation  or  stasis  of  the  blood  in  the 
vessels  of  the  injured  area — I  say  frequently,  for  at  other  times  little 
or  no  absolute  arrest  is  seen  in  the  vessels.  Accompanying  this  stage, 
although  observers  employing  other  and  chemical  methods  of  inflicting 
injury  have  in  general  omitted  to  call  attention  to  the  fact,  there  is 
already  a  considerable  oozing  or  exudation  of  clear  fluid  from  the  "'^ound ; 
there  is,  that  is  to  say,  an  outpouring  of  lymph,  and  that  apparently  from 
the  distended  vessels.  Now,  with  the  slowing  of  the  stream  the 
leucocytes,  accumulated  next  to  the  walls  of  the  small  veins  and  within 
the  capillaries,  pass  from  the  interior  to  the  exterior  of  these  vessels ; 
and,  if  the  process  be  studied  carefully  with  a  higher  power,  it  can 
be  seen  that  this  mode  of  passage  is  of  an  active,  or  apparently  active 
nature.^  A  series  of  leucocytes  can  be  distinguished  some  of  which  are 
rounded  or  flattened  in  immediate  contact  with  the  wall  of  the  vein ; 
others  possess  a  prolongation  passing  into  the  wall ;  in  others,  again  (or 
in  the  former  if  they  be  watched  in  the  fresh  specimen),  the  prolongation 
enlarges  on  the  outer  side  of  the  small  vessel  while  the  portion  of  the 
leucocyte  within  the  vessel  becomes  smaller.  The  final  phase  of  this  act 
of  diapedesis  is  that  the  whole  leucocyte  passes  through,  and  is  found  in 
the  lymph  spaces  around  the  vessel  wall.  This  process  of  diapedesis 
may  be  so  general  that  in  the  course  of  five  or  six  hours  all  the  small 
veins  of  the  region  show  a  crowd  of  leucocytes  situated  along  their  outer 
surface.  With  these  a  greater  or  less  number  of  red  corpuscles  may 
also  make  their  escape. 

Although  the  capillaries,  from  the  very  smallness  of  their  diameters, 
do  not  show  the  so-called  "  margination"  of  leucocytes,  nevertheless  this 
same  process  of  diapedesis  may  occur  at  various  points  along  their  course, 
so  that  outside  the  capillaries  also  a  fair  number  of  the  same  small  highly- 
refractile  cells  endowed  with  amoeboid  movements  can  be  observed. 

In  this  modification  of  Cohnheim's  experiment  a  further  stage  is  to  be 
recognised.  While  at  first  the  fluid  exuded  was  clear  and  relatively  free 
from  cells  and  cell  debris,  now,  as  the  inflammatory  process  continues,  an 
increasing  number  of  leucocytes  is  contained  in  the  exudation.     The 


inflicted  upon  the  carapace,  the  leucocytes,  previously  unadhesive,  soon  show  the  tendency 
to  adhere  to  the  walls  of  the  body  cavity  beneath  the  region  of  injury  and  elsewhere. 

1  The  process  can  be  fully  made  out  if  at  this  stage  the  wounded  region  be  removed, 
fixed  immediately  in  weak  osmic  acid,  aud  prepared  fur  examination  by  the  higher 
powers  of  the  micruscupe. 


TO 


SYSTEM  OF  MEDICINE 


leucocytes  >  not  remain  in  the  immediate  neighbourhood  of  the  vessels, 
but  many  of  them  pass  on  to  the  injured  surface ;  still  it  would  seem  by 
active  amoeboid  movement.  Thus  at  the  end  of  six  hours  this  surface 
may  be  covered  by  a  serum  or  fluid  in  w  bich  are  great  numbers  of  these 
leucocytes.  Here  then  we  have  the  first  step  towards  the  formation  of 
a  scab  or  provisional  protective  covering  to  the  wound. 

Further  observations  cannot  well  be  carried  out  in  the  pithed  and 
curarised  frog ;  but  if  an  unpithed,  non-curarised  animal  be  taken,  and 
the  observations  upon  the  earlier  stage  be  neglected,  it  can  be  made  out 
that  if  irritant  matter  do  not  find  entry  into  the  wound  the  process  may 
be  arrested  at  this  point;  the  leucocytes  upon  the  surface  may  break 
down,  and  with  their  breaking  down  and  the  formation  of  fibrin  a  soft 
scab  be  formed :  the  stasis  of  the  blood  in  the  distended  vessels  may  be 
followed  by  a  re-establishment  of  the  current  and  slow  return  of  the 
vessels  to  their  former  calibre,  while  beneath  the  thin,  soft  scab  the 
epithelial  cells  rapidly  proliferate.  Within  twenty-four  hours  there  may 
be  abuadant  evidence  of  this  new  growth  of  the  epithelium  tending 
to.  encx'oach  upon  and  cover  the  wound.  At  the  same  time  the  region 
becomes  less  and  less  populated  with  leucocytes,  so  that  —  not  to  enter 
fully  at  this  point  into  the  reparative  process  —  within  sixty  hours  the 
region  may  show  little  sign  of  the  injury  and  consequent  inflammation. 

On  the  other  hand,  if  irritants  of  a  microbic  nature  enter  the  wound 
the  process  may  extend,  as  in  inflammation  of  the  cornea.  More  especially 
if  the  water  in  which  the  frog  is  kept  become  foul,  there  is  a  tendency 
in  the  inflammatory  processes  to  spread ;  and  in  the  cells  of  the  central 
area,  both  flxed  and  migrated,  to  break  down,  leading  to  the  formation  of 
a  spreading  ulcer.  The  steps  of  this  sequence  of  affairs  it  is  difficult  to 
follow  by  continuous  microscopic  examination,  partly  on  account  of  the 
increased  opacity  of  the  region,  partly  because  the  process  extends  over 
days  rather  than  hours.  Here,  therefore,  I  merely  mention  this  possible 
extension  of  the  change  with  its  main  naked-eye  appearances. 

It  is  not  possible  by  continuous  observation  to  make  out  the  steps  of 
this  more  extensive  inflammation  characterised  by  excessive  emigration 
of  leucocytes  and  destruction  of  these  together  with  the  fixed  cells  of  the 
tissue  —  the  pyogenetic  inflammation.  Several  observers,  however,  have 
followed  its  successive  stages  by  means  of  examination  of  affected  tissues 
at  successive  intervals  after  the  infliction  of  injury. 

The  Experimental  Production  of  Suppurative  Inflammation.  —  While, 
as  shown  by  Councilman,  Grawitz  and  de  Barry,  Straus,  Leber  and 
others,  a  suppurative  inflammation  may  under  certain  conditions  be 
brought  about  experimentally  by  the  action  of  chemical  irritants,  such 
as  mercury  and  turpentine ;  yet  under  ordinary  pathogenic  conditions 
suppuration  is  induced  by  the  growth  of  micro-organisms  within  the 
tissues.  Hence  it  is  better  to  study  the  conditions  as  induced  by  the 
inoculation  of  pus-producing  microbes  into  one  or  other  tissue.  A  very 
full  series  of  observations  upon  the  development  of  abscesses  through  the 
agency  of  the  Staphylococcus  pyogenes  aureus  has  been  made  by  Hohn- 


INFLAMMA  TION 


7» 


feldt.  He  employed  rabbits,  and  incculated  small  quantities  of  pure 
cultures  of  the  microbe  subcutaneously. 

Four  hours  after  inoculation  the  vessels  of  the  region  were  found 
densely  filled  with  corpuscles,  and  in  them  a  commencing  margination  of 
the  white  corpuscles  was  discernible.  Leucocytes  were  present  within 
the  tissue  in  numbers  greater  than  normal ;  although,  compared  with  later 
stages,  they  were  infrequent  They  were  of  two  kiuf^s — the  mono- 
nuclear in  the  majority,  the  polynuclear  (or  more  truly  the  form  with 
polymerous  nucleus)  in  lesser  numbers;  both  forms  were  congregated 
mainly  around  the  line  of  entrance  of  the  injecting  needle.  Many  of 
the  connective  tissue  cells  were  so  swollen  as  to  be  rounded  rather  than 
flattened.  The  injected  cocci,  lying  in  the  lymph  spaces,  were  scattered 
through  the  tissue ;  in  part  free,  in  part  already  ingested  by  cells,  not 
only  by  the  leucocytes,  but  also  by  connective  tissue  cells :  the  number 
within  leucocytes  was  not  inconsiderable. 

Preparations  made  at  the  end  of  ten  hours  showed  the  same  conditions, 
but  more  distinctly.  There  was  ample  evidence  of  migration  of  the 
leucocytes,  margination  in  the  congested  vessels,  various  stages  of  passage 
through  the  vascular  walls,  and  large  collections  of  the  cells  in  the  peri- 
vascular Ij^mph  spaces ;  from  these  they  spread  into  the  spaces  between 
the  bundles  of  connective  tissue  fibrils.  The  cocci  lay  in  the  lymph 
spaces  and  were  increased  in  number,  and  the  massing  of  leucocytes  cor- 
responded in  position  to  the  accumulation  of  microbes.  In  these  regions 
the  leucocytes  were  mainly  polymerous  or  multinuclear,  but  in  the  boun- 
dary zone  away  from  the  cocci  the  uninuclear  form  predominated. 

At  the  end  of  twenty  hours  there  was  further  accentuation  of  these 
conditions.  As  yet  an  abscess  proper  had  not  formed,  but  enormous 
numbers  of  leucocytes  were  present,  and  also  of  mit.ococci;  the  fibrillao 
of  connective  tissue  were  widely  separated  by  the  collections  of  leuco- 
cytes, and  these  cells  clustered  round  and  hid  the  connective  tissue  cells. 

With  the  completion  of  forty-eight  hours  a  well-defined  abscess  had 
formed,  separated  sharply  from  the  surrounding  healthy  tissue.  The 
centre  of  the  abscess  was  seen  to  consist  of  densely-packed  leucocytes 
mingled  with  largo  growths  of  cocci.  These  leucocytes  were  almost 
entirely  "  miiltinuclear ; "  and  in  this  central  area  the  nuclei  of  some 
showed  fragmentation.  Neither  leucocytes  nor  connective  tissue  cells 
showed  the  slightest  indication  of  mitosis.  In  the  central  area  all  traces 
of  the  previous  capillaries  had  disappeared ;  in  the  peripheral  zone  they 
were  easily  recognisable,  being  fully  injected  and  showing  a  marginal 
disposition  of  their  leucocytes,  many  of  which  could  be  seen  (in  osmio 
acid  preparations)  fixed  in  the  process  of  diapedesis. 

The  majority  of  the  cocci  lay  in  these  leucocytes.  Even  whore  the 
colonies  of  the  microbes  were  thickest  there  the  majority  were  intra- 
cellular. Passing  towards  the  periphery  the  number  of  cocci  became 
smaller  and  smaller.  At  the  periphery  they  could  Ix?  seen  not  only  to 
bo  intracellular,  but  also  free  in  the  lymph  spaces ;  and  Hohnfeldt,  with 
other  observers,  saw  them  definitely  grouped  within  the  endothelial  cells 


72 


SYSTEM  OF  MEDICINE 


of  the  peripheral  vessels.  Thus  it  may  be  noted  that  at  this  stage  the 
proliferating  microbes  extended  into  the  healthy  tissues  outside  the 
abscess. 

In  the  centre  of  the  abscess  the  original  tissue  had  wholly  disappeared ; 
nearer  the  periphery  light  streaks  and  bundles  of  the  disintegrating 
fibrillae  could  be  recognised  between  the  leucocytes. 

Not  till  about  the  tenth  day  did  new  growth  of  tissue  begin  to  show 
itself.  During  the  preceding  six  days  there  had  been  more  breaking 
down  of  the  polynuclear  leucocytes,  characterised  by  fragmentation  of  the 
nuclei  and  by  fatty  degeneration  of  the  cell  substance.  But  by  the  tenth 
day  the  periphery  had  begun  to  assume  the  appearance  of  granulation 
tissue ;  it  contained  numerous  capillaries  and  new-formed  connective  tis- 
sue with  characteristic  epithelioid  cells  or  fibroblasts  possessing  large  oval 
pale  staining  nuclei.  In  these  cells,  as  in  the  connective  tissue  cells  of 
the  surrounding  healthy  tissue,  could  the  numerous  steps  of  indirect  cell 
division  be  made  out.  In  this  granulation  tissue  cocci  were  absent  and 
leucocytes  were  infrequent.  In  the  soft,  cheesy  central  area  masses  of 
cocci  were  still  present.  Whether  these  were  living  or  dead  Hohnfeldt 
did  not  determine ;  he  inferred  (what  has  since  been  proved  by  several 
observers  to  be  an  unsafe  inference)  that  inasmuch  as  they  stained  well 
with  aniline  dyes  they  were  alive. 

Thus,  to  sum  up  Hohnfeldt's  observations,  the  processes  occurring  in 
a  suppurative  inflammation  that  ends  in  healing  are  the  following :  — 

1.  Congestion  of  the  region  of  invasion,  with  marginatiou  of  the 
leucocytes. 

2.  Collection,  in  the  region,  of  uninuclear  leucocytes ;  then  diapedesis 
of  leucocytes  with  polymerous  nuclei :  multiplication  of  the  cocci. 

3.  Ingestion  of  large  numbers  of  the  microbes  by  the  polymerous 
leucocytes  and  other  cells,  including  the  endothelial  cells  of  the  vessel 
walls. 

4.  Increasing  immigration  of  leucocytes  until  the  tissue  becomes 
densely  packed.  This  is  accompanied  by  a  yet  greater  proliferation  of 
the  microbes,  whicli  extend  (i.e.  are  carried  by  lymph  streams  or  by  cells) 
into  the  region  outside  the  developing  al)sces8. 

6.   Destruction  of  tlu!  tissue  of  the  aft'ectiMl  part. 

6.  Degeneration  of  the  leucocytes  within  the  sharply-defined  abscess. 

7.  Eventual  proliferation  of  the  connective  tissue  at  the  periphery  of 
the  abscess ;  formation  of  fibroblasts  in  the  highly  vascular  surrounding 
zone;  cicatrisation  and  encapsulation  of  the  debris  of  the  leucocytes 
and  micrococci. 

There  are  not  a  few  points  in  connection  with  these  observations  of 
Hohnfeldt  that  deserve  discussion ;  very  possibly  ho  has  misinterpreted 
certain  of  the  appearances  seen  by  him.  On  the  whole,  however,  he 
draws  a  ftill  and  accurate  picture  of  the  successive  stages  of  suppurative 
inflammation,  and  I  may  defer  discussion  to  a  later  review  of  the  action 
of  the  leucocytes  and  of  the  formation  of  fibrous  tissue  respectively. 

However,  before  leaving  this  general  description  of  the  scries  of 


INFLAMMA  TION 


73 


anatomical  changes  induced  by  injury,  there  is  another  phase  of  the 
inflammatory  process  set  up  by  pathogenic  micro-organisms  which  must 
not  be  passed  over  —  I  refer  to  those  cases  in  which,  instead  of  ending 
in  repair,  there  is  extension  and  generalised  disease.  The  stages  pre- 
ceding extension  vary  with  the  nature  of  the  microbe ;  thus,  in  some 
cases,  the  reaction  to  the  invasion  of  the  microbe  is  mainly  leucocytic 
(as  with  inoculations  of  the  micrococci  of  suppuration),  in  others  it  is 
mainly  exudative  or  serous,  the  congestion  of  the  vessels  being  followed 
by  abundant  exudation  of  serum  into  the  tissues.  This  is  the  case  in 
inoculation  of  animals  — such  as  rabbits,  guinearpigs  and  fowls  —  with 
cultures  of  micro-organisms  which  are  peculiarly  virulent  in  their  bo- 
haviouf  towards  these  animals.  Such  a  serous  or  exudative  inflamma- 
tion is,  for  instance,  well  seen  if  the  vibrio  Metschnikovi  be  inoculated 
into  the  pectoral  muscles  of  a  fowl.  Within  twelve  hours,  it  may  be, 
the  seat  of  inoculation  becomes  greatly  swollen,  and  on  section  is  found 
reddened  and  congested;  while  from  it  drains  an  abundance  of  relatively 
clear,  faintly-reddish  serum  containing  but  a  few  leucocytes. 

In  such  a  case  as  this  the  micro-organisms  appear  to  pass  with  ease 
from  the  centre  of  infection  into  the  surrounding  tissues,  and  thence 
into  the  lymphatics  and  general  circulation,  whence  they  may  be 
obtained  within  twenty-four  homs.  Where  there  has  been  a  well- 
marked  abscess  formation  in  the  region  of  invasion  there,  as  already 
indicated,  it  is  true  that  the  microbes  may  be  found  outside  the  abscess 
at  a  fairly  early  period ;  but,  in  the  main,  proliferation  is  limited  to  the 
abscess,  and  the  blood  remains  free  and  sterile.  Under  certain  condi- 
tions of  great  virulence  of  the  pyogenic  microbes  it  is  found  that  as  the 
abscess  extends  it  becomes  ill-defined  —  there  is  no  shcarp  demarcation 
between  the  collected  leucocytes  and  the  surrounding  tissue;  the 
columns  of  leucocytes  spread  indefinitely  from  the  centre,  and  numerous 
micrococci  are  intermingled  with  them.  Where  this  is  the  case  there 
is  a  marked  tendency  for  the  microbes  to  find  their  way  into  the  general 
circulation  from  this  irregular  peripheral  extension  along  the  lynipliatio 
spaces,  and  to  set  up  a  condition  of  septicajmia  as  in  the  more  serous 
inflammation  described  above. 

Septicemia,  or  the  passage  of  micro-organisms  into  the  blood,  with 
all  the  results  of  sucli  a  passage  —  the  condition  which  sundry  French 
observers  have  described  as  inflammation  of  the  blood  —  is  dealt  with 
in  another  article.  In  septicemia  we  pass  beyond  the  local  response  to 
injury,  we  deal  with  a  state  of  general  systemic  disturbance.  Never- 
theless certain  phases  of  the  septicajmic  condition  throw  light  upon  tho 
inflammatory  process. 

In  the  first  place,  it  is  of  interest  to  note  that  when  tho  infective 
micro-organisms  and  their  products  are  within  tho  vessels  they  fail  to 
mduco  the  cardinal  symptoms  of  inflammation.  They  do  not  lead  to 
exudation  of  fluid  from  tlie  blood  or  to  wide-spread  diapedesis  of  leuco- 
cytes. The  stimulus,  whatever  it  be,  wliicl)  leads  to  these  phenomena  at 
the  point  of  iuvasioa  is  no  lou^jor  called  into  activity  when  the  uoxa  is 


74 


SYSTEM  OF  MEDICINE 


within  the  circulatory  apparatus.  This  is  the  reverse  of  what  might  be 
expected  if  the  inflammatory  process  were  primarily  due  to  a  modification 
of  the  endothelium  of  the  vessel  walls  by  the  irritant,  a  modification  pas- 
sively permitting  the  exudation  and  passage  outwards  of  the  leucocytes. 

The  statement  that  infective  micro-organisms  and  their  products 
circulating  within  the  ulood  fail  to  induce  inflammatory  changes,  would 
seem  to  need  modification  when  the  development  of  metastatic  abscesses 
is  taken  into  account.  But  a  study  of  the  mode  of  pi-oduction  of  these 
abscesses  shows  that  the  statement  still  holds.  Such  abscesses  originate 
round  emboli  of  pyogenic  micro-organisms  in  the  capillaries.  Sundry 
cocci  are  arrested  in  the  capillary,  proliferate  and  fill  the  vessel.  It  is 
only  when  a  minute  vessel  is  thus  occluded  that  the  abscess  process 
begins,  that  is  to  say,  when  by  this  occlusion  the  vessel  has  become 
extravascular ;  and  while  it  is  true  that,  primarily,  the  arrest  of  patho- 
genic microbes  within  the  capillaries  is  often  associated  with  a  small 
accumulation  of  intravascular  leucocytes  and  with  degenerative  changes 
in  the  vascular  endothelium,  the  metastatic  abscess,  as  such,  forms  not 
by  accumulation  of  leucocytes  in  the  occluded  vessel,  but  around  it ; 
the  leucocytes  emigrating  from  surrounding  capillaries. 

Inflammatory  Fever.  —  In  the  second  place,  through  this  study  of 
advancing  inflammation  it  is  of  interest  to  trace  the  very  close  relation- 
ship that  exists  between  inflammation  and  fever.  Besides  the  local 
changes  here  described,  local  injury  is  accompanied  by  systemic  dis- 
turbances.   These  may  be  slight  or  grave. 

Take,  for  instance,  progressive  abscess  formation,  or  follow  the 
development  of  a  malignant  carbuncle  in  man.  At  first  the  reaction 
is  purely  local,  but  very  soon,  long  before  any  of  the  micro-organisms 
are  capable  of  detection  in  the  blood,  thero  is  exaltation  of  temperature 
and  a  slight  febrile  state,  the  fever  becoming  more  and  more  evident  as 
the  local  process  becomes  more  and  more  extensive,  until  with  the 
detection  of  the  microbe  in  the  blood  the  most  severe  fever,  with  con- 
stitutional disturbance,  sets  in.  Local  inflammation,  then,  without  any 
other  possible  explanation  than  either  tlie  nervous  irritation  to  which 
it  may  give  rise,  or  the  passage  into  the  general  circulation  of  the 
soluble  products  of  bacterial  growth  and  tissue  destruction,  or  both, 
may  load  to  the  development  of  the  febrile  state.  How  large  a  share  is 
l)laycd  by  these  two  possible  factors  it  is  difficult  to  say.  That 
bacterial  products  injected  into  the  circulation  lead  to  the  rapid  pro- 
duction of  the  febrile  state  wo  have  ample  evidence ;  but  whether  those 
act  directly  by  inducing  increased  cellular  activity,  or  indirectly  by 
stimulating  the  censbral  centres,  wo  cannot  absolutely  say.  As  yet  wo 
have  little  accurate  knowledge  of  tlie  ]iarts  played  by  the  nervous 
system  in  the  devolo])mpnt  of  the  febrile  state.  This,  however,  may 
safely  be  declared,  that  the  more  we  study  the  continued  fevers  the  more 
do  we  discover  that  these  commence  by  a  local  inflammatory  disturbance. 
The  continued  fevers  are  the  continuance,  or  rather  the  extension,  of  a 
primarily  localised  inflammatory  lesion.     [Vule  art.  on  "  Fever."] 


INFLAMMA  TION 


75 


Summary  of  the  Facts  thus  far  brought  forward. 

The  main  facts  gathered  thus  far  concerning  the  inflammatory  pro- 
cess, and  the  conclusions  to  be  drawn  therefrom,  may  now  be  placed  in 
order  before  I  discuss  in  detail  the  various  factors  in  the  process.  They 
are  — 

1.  Injury,  when  it  is  not  so  widespread  and  severe  as  to  lead  to  the 
death  of  the  individual,  is  followed  by  a  reaction  on  the  part  of  the 
organism. 

2.  In  unicellular  organisms  the  continued  vitality  of  the  individual 
after  injury,  and  in  multicellular  organisms  the  vitality  of  the  indi- 
vidual cells,  are  dependent  primarily  upon  the  persistence  of  the 
nucleus ;  if  this  be  destroyed  or  removed  the  rest  of  the  cell  is  incapa- 
ble of  complete  restitution  and  continued  growth. 

3.  In  unicellular  organisms  the  reactive  process  is  twofold,  and  con- 
sists of  (a)  destruction  or  removal  of  the  irritant;  destruction  being 
brought  about  by  a  process  of  intracellular  digestion,  removal  by  extru- 
sion of  the  irritant :  (p)  new  growth  of  the  organism. 

4.  This  response  to  injury  on  the  part  of  unicellular  organisms  is 
essentially  reparative. 

5.  In  multicellular  organisms,  with  division  of  labour  among  ^e 
constituent  cells  of  the  individual,  there  is  a  separation  of  functions ; 
the  twofold  reaction  to  local  injury  is  yet  more  clearly  mai^ked ;  but 

(a)  The  destruction  or  removal  of  the  irritant  is  in  the  main  accom- 
plished by  the  wandering  cells  of  mesoblastic  origin. 

(6)  The  new  growth  to  replace  the  tissue  destroyed  by  the  irritant 
proceeds  in  the  main  from  the  fixed  cells  of  the  tissue. 

0.  Ascending  the  scale  of  multicellular  organisms,  a  division  of 
labour  and  differentiation  of  function  is  discoverable  among  the  wander- 
ing mesoblastic  cells.  Whereas  in  the  lower  forms  of  the  Metazoa  one 
type  of  leucocyte  alone  is  present,  in  the  higher  forms  two  or  more 
varieties  can  be  distinguished  which  possess  different  properties  and 
act  differently  towards  irritants  introduced  into  the  system. 

7.  According  to  the  nature  of  the  irritant  causing  the  injuiy,  the 
leucocytes  are  actively  attracted  in  greater  or  less  numbers  to  the 
region  of  injury,  surround  the  irritant,  and  remove  or  destroy  it  by 
means  very  similar  to  those  employed  by  unicellular  organisms.  Where 
the  irritant  is  present  in  the  form  of  discrete  particles,  there  some  at 
least  of  the  leucocytes  may  incorporate  the  particles,  and  remove  them 
or  destroy  them  by  a  process  of  digestion.  Others  of  the  leucocytes  in 
the  higher  Metazoa  never  act  thus  as  phagocytes;  nevertheless  they  are 
equally  attracted  to  the  focus  of  inflammation,  and  presumably  tend  to 
counteract  the  irritant  by  some  other  (extracellular)  means. 

8.  While  to  the  wandering  cells  appears  to  bo  allotted  the  main 
duty  of  removing  dpletori()\is  and  irritant  matters,  certain  of  the  fixed 
cells  of  the  orgatiism,  notably  the  endothelial  cells  of  the  vcssj'Is,  cnn 
also  exert  these  functions. 


76 


SYSTEM  OF  MEDICINE 


9.  Among  the  very  large  number  of  Metazoan  forms  in  which  no 
complete  vascular  system  is  present,  this  attraction  of  the  leucocytes  to 
the  region  of  injury  is  at  first  the  sole  response  to  injury.  At  a  later 
period  proliferation  of  the  fixed  cells  occurs  in  the  neighbourhood  of 
the  injury. 

10.  Among  the  higher  Metazoa,  in  which  there  is  a  well-developed 
vascular  system,  the  determination  of  leucocytes  to  the  region  of  irrita- 
tion still  continues,  and  is  in  fact  markedly  aided  by  the  participation 
of  the  vessels  in  the  inflamirntory  process. 

11.  The  vascular  phenoraena  in  inflammation  may  be  regarded  as 
serving  two  main  purposes  —  (a)  the  pouring  out  of  increased  fluid  into 
the  injured  area ;  (6)  the  afflux  and  diapedesis  of  leucocytes. 

12.  Even  in  the  highest  Metazoa,  possessing  fully-developed  vascular 
systems,  the  response  to  injury  in  a  non-vascular  area,  such  as  the 
cornea,  may  be  associated  with  no  change  in  the  surrounding  vascular 
areas,  but  purely  with  a  determination  to  the  injured  area  of  leucocytes 
already  free  in  the  surround)  :ig  tissues. 

13.  The  second  phase  of  the  inflammatory  process,  that  of  tissue 
repair,  but  very  rarely  occurs  without  evidence  of  previous  migration 
of  leucocytes  and  exudation  from  the  congested  vessels. 

14.  A  comparative  study  leads  inevitably  to  the  conclusion  that  the 
determination  of  leucocytes  to  the  region  of  injury  is  the  most  constant 
and  most  characteristic  early  response  to  injury  recognisable  through- 
out the  Metazoa,  and  that  it  must  be  regarded  as  the  most  important 
factor  in  the  first  stage  of  the  inflammatory  process.  The  vascular 
phenomena  noticeable  in  the  higher  Metazoa  must  be  regarded  as  a 
second  and  highly  important  factor  of  later  development  and  adjuvant. 
New  tissue  formation  is  the  prominent  characteristic  of  the  later  stages 
of  the  process. 

15.  As  among  the  Protozoa,  so  in  the  Metazoa,  the  response  to 
injury  is  consistently  an  attempt  to  repair  the  injury. 

This  general  survey  of  the  response  to  injury  throughout  the  animal 
kingdom  demonstrates  most  clearly  that  the  same  broad  principles,  the 
same  methods  of  defence  and  repair  on  the  part  of  the  organism,  are 
called  into  activity  from  the  lowliest  forms  to  the  higliest ;  that,  in  fact, 
no  line  can  be  drawn  to  separate  one  set  of  phenomena  as  truly  inflam- 
matory from  another  set  which,  while  also  a  response  to  injury,  are  non- 
inflammatory. Although  it  is  true  that  the  term  inflammation  implies 
a  reddening  and  congestion  of  the  vessels,  we  find  upon  closer  exam- 
ination that  this  reddening  and  congestion  is  not  the  fundamental  but  a 
superadded  feature  in  the  process  of  repair  of  injury  —  a  feature  super- 
added as  the  organism  advances  in  its  place  in  the  animal  kingdom. 
Thus  if  we  are  to  comprehend  the  process  satisfactorily  we  must  pass 
beyond  the  narrower  acceptation  of  the  term. 

Having  thns  sketched  broadly  the  general  phenomena  of  the  inflam- 
matory process,  it  will  bo  well  now  to  describe  in  fuller  detail  the  factors 
of  this  process  among  the  higher  vertebrata,  and  to  bring  together  the 


INFLAMMA  TION 


11 


more  important  results  of  the  study  of  the  respective  functions  of  the 
wandering  cells,  the  vessels,  the  fixed  cells,  and  the  nervous  system 
in  inflammation. 


PART  11.  —  The  Factors  in  the  Inflammatory  Process 


Chapter  1. — The  Part  played  by  the  Leucocytes 

The  Leucocytosis  of  Inflammation.  —  As  I  have  already  shown,  there 
is  more  than  one  form  of  leucocyte  in  the  mammalian  organism, 
and  the  several  forms  evidently  possess  different  attributes,  and  act 
differently  in  the  reaction  to  injury.  Inasmuch  as  these  forms  have 
been  variously  classified  —  so  variously,  in  fact,  that  it  is  often  far  from 
easy  to  collate  the  various  descriptions,  and  to  discuss  the  forms  distin- 
guished by  one  observer  in  the  terms  of  another — it  is  necessary  to 
give  the  chief  classifications  of  them,  and  their  relations. 

The  first  to  discriminate  between  the  forms  of  white  corpuscles  in 
the  blood  was  Wharton  Jones  so  long  ago  as  1846.  He  drew  a  dis- 
tinction between 

A.  GranuWlta    jSr^"ar. 

B.  "  Nucleated  "  cells — Non-granular. 

His  observations,  together  with  those  of  Rindfleisch  in  1861  and 
1863,  were  confirmed  and  advanced  by  Max  Schultze,  who  made  out  the 
following  forms :  — 

1.  Small  round  cells  with  round  nucleus  and  little  clear  protoplasm. 

2.  Larger  cells  with  round  nucleus  and  more  clear  protoplasm. 

3.  Cells  with  finely  granular  protoplasm,  and  one,  two,  or  more  nuclei. 

4.  Cells  with  coarse  granules  in  the  protoplasm.  . 

The  distinctions  drawn  were,  so  far,  purely  morphological ;  and  very 
little  notice  was  taken  of  these  varieties  for  a  long  period  until  Ehrlich, 
in  a  notable  series  of  papers  extending  from  1878  to  1887,  drew  atten- 
tion to  the  fact  that  the  wandering  cells  of  the  organism  react  diversely 
towards  the  different  aniline  dyes  and  possess  diverse  tinctorial  affinities 
indicating  chemical  differences  in  the  nature  of  certain  constituents 
of  the  cell  bodies.  The  granules  of  the  i)rcvious  observers  were  found 
to  bo  variously  affected  by  the  dyes  emjiloyed ;  they  were  shown  not  to 
be  fatty,  but  —  as  Ehrlich  put  it  —  of  the  nature  of  a  glandular  excre- 
tion ;  *  and  comparing  the  effects  of  the  two  groups  of  aniline  colours 
—  that  in  which  the  dye  is  associated  with  the  acid  constituent  of  the 
salt,  and  that  wherein  the  dye  forms  the  base  (the  "acid"  and  **  basic" 

•  .1.  Woiss  lias  Btudlod  tho  micro-ohemlcal  reactions  of  the  oosinopbilous  Rranulns, 
and  coiinludcH  that  tlioy  aro  of  allxuiiinoid  nature  ;  asthoy  were  found  not  to  be  digested 
in  gastric  juicu  ho  would  ally  thum  witli  tho  uucleins. 


78 


SYSTEM  OF  MEDICINE 


aniline  dyes  respectively)  —  lie  made  out  the  existence  of  five  forms  of 
granulation  associated  with  as  many  varieties  of  wandering  cells.  His 
table  of  cells  according  to  their  granulation  is  as  follows :  — 

a.  Granulation  —  Eosinophile.  —  Cells  frequently  in  horse's  blood,  present  con- 
stantly in  small  numbers  in  human  blood ;  numerous  in  medulla  of 
bones  of  rabbits,  dogs,  guinea-pigs,  etc.  Stain  deeply  with  acid  aniline 
dyes.    Granules  large  and  coarse. 

/3.  Granulation  —  Amphophile.  —  Cells  frequent  in  rabbits  and  guinea-pigs  in 
blood ;  present  also  in  medulla  of  bones.  Stain  both  with  acid  and  basic 
dyes.    Granules  fine. 

>.  Granulation  —  Basophile. — Largo  cells  found  in  the  connective  tissue, 
from  the  frog  upwards,  "Mastzellen"  ;  in  blood  of  man  only  in  cer- 
tain cases  of  Leucaemia.  Stain  only  with  basic  dyes.  Granules 
coarse. 

3.  Granulation  —  Fine  Basophile. — The  "mononuclear"  leucocyte  of  human 
blood.    Granulation  fine.     Stain  with  basic  dyes. 

e.  Granulation  —  Neutrophile.  —  The  most  frequent  leucocyte  of  human 
blood,  "  polynuclear."  Stain  only  in  neutral  dyes  —  not  in  acid  or 
basic. 

While  Ehrlich  and  his  pupils,  and  Rieder,  have  done  much  to  throw 
light  upon  the  relative  numbers  of  the  leucocytes  possessing  these  different 
granulations  in  different  diseases,  they  have  accomplished  little  in  dis- 
covering the  origin  of  the  various  forms,  their  functions,  or  their  relation- 
ships. We  owe  the  first  satisfactory  studies  upon  the  properties  of  the 
different  forms  to  Metschnikott",  who,  at  an  early  period  in  his  long- 
continued  and  wonderful  series  of  researches  upon  Phagocytosis,  made 
out  that  the  different  wandering  cells  of  the  body  act  differently  towards 
microbic  and  other  foreign  particles  introduced  into  the  organisms.  Thus 
he  was  led  to  draw  a  distinction  between  — 

1.  Lymphocytes  —  immature  leucocytes. 

2.  Large  hyaline  cells,  mononuclear,  phagocytic,  "macrophages."* 

3.  Smaller  neutrophile  cells,  polynuclear,  *'  microphages." 

4.  Eosinophile  leucocytes  —  not  phagocytic."'' 

Quite  recently  the  admirable  researches  of  Prof.  Sherrington,  and  of 
Dr.  Kanthack  and  Mr.  Hardy,  have  appeared  which,  starting  on  the 
groimdwork  laid  down  by  the  older  observers,  have  made  a  notable 
advance  in  the  determination  oi  the  function  of  the  various  forms  of 
wandering  cells  in  inflammatory  and  other  conditions.    The  observations 


1  While  acknowledging  that  a  certain  amount  of  convonicneo  attends  the  employ- 
ment  of  these  terms,  "  macrophage"  and  "  raicrophago,"  I  cannot  but  agroo  with  Pro- 
fessor Hurdon-Sanderson  that  they  are  utterly  l)ai'l)aric. 

2  While  this  article  was  passing  through  tlio  press,  M.  Meanil,  a  pupil  of  Motschnikoff, 
has  stated  that  eosinopliilous  cells  can  occasionally  act  as  pliagocytos.  The  statement  is 
contrary  to  MetschnikofT's  previous  observations  and,  I  may  add,  contrary  to  general 
experience.  Until  furtliur  uuuliriuatury  obtiurvatiuuu  huvu  buou  uadu,  I  am  uut  prepared 
tu  accept  the  statement. 


INFLAMMATION 


79 


of  Kanthack  and  Hardy  are  especially  full,  and  I  shall  have  occasion  to 
refer  continually  to  their  results.  In  the  mfeantime  it  may  be  said  that 
they  materially  simplify  the  classification  given  by  Ehrlich,  by  dividing 
the  leucocytes  thus :  — 

2:  ^fn^'SJaf  '  }  0^P^«  ««"«•    Staining  with  acid  dyes. 
4:Rne^'^SM*'}Ba«)plulecell8.    Staining  with  basic  dyes. 

6.  Hyaline  cells, 
i).  Lymphocytes. 

Their  coarsely  granular  oxyphile  cells  are  the  eosinophile  cells  of 
most  writers ;  their  finely  granular  are  the  neutrophile  and  amphophile 
of  Ehrlich.  They  prove  conclusively  that  Ehrlich's  neutral  stain  is  in 
no  sense  to  be  regarded  as  such,  but  must  be  considered  as  an  acid  dye. 

It  is  now  possible  to  collate  these  various  classifications,  and  in  this 
way  to  begin  to  study  the  functions  of  the  various  forms  with  a  clear 
appropriation  of  the  terms  employed  in  the  following  paragraphs. 


Collation  of  the  different  Classifications  of  the  Varieties  of  Leucocytes. 


Kanthack  and  Uardy. 

Ehrlich. 

Metschnikoff. 

Max  SchulUe. 

Wharton  Jonca. 

Lymphocyte. 

Lymphocyte. 

Lymphocyte. 

Small  round  cell  I. 

(Non-granular 
t     nucleated  cells. 

Hyaline  cell. 

Macrophogocyto. 

Large  round  cell  H. 

Coarsely  granular 

Eosinophile  coll. 

Eosinophile  cell. 

Cells  with  coarsely 

Grannie  cells, 

oxyphile. 

granular    proto- 
plasm. 

coarsely  granular. 

Finely  granular  J 
oxyphile.           ( 

Neutrophil  ,^^ 
Amphophile 

Miorophogocyte. 

Cells    with    finely 

Granule  cells,  finely 

granular    proto- 

granular. 

plasm. 

Coarsely  granular 

Basophile  cell  with 

basophile. 

y  granulation. 
Maotzellen. 

. 

Finely    granular 

Basophile  cell  with 

Cells    with    finely 

?  Granule  cells,  finely 

basophile. 

J  granulation. 

granular    proto- 
plasm. 

granular. 

LymphocyU.  —  Immature  leucocyte  ;  round  nucleus  deeply  staining  ;  scanty  pro- 
toplasm ;  increased  in  number  after  food ;  diminished  after  starvation ; 
indi&tii.guishable  from  small  elements  of  lymphoid  tissue.  Not  phagocytic ; 
variable  in  number ;  not  amoeboid ;  may  form  up  to  30  per  cent  of  tho 
leucocytes  present  in  human  blood. 

Uyaline  Cell.  —  Kound  or  kidney-shaped  nucleus  of  slight  staining  power ; 
abundant  protoplasm ;  hyaline ;  non-granulated ;  actively  amooboid  and 
phagocytic  ;  rare  in  blood  (2  per  cent)  ;  abundant  in  coolomic  fluid. 
Nuclei  have  been  s».  en  to  undergo  mitosis. 

Coarsely  Granular  Oxyph  'le.  —  Large  horseshoe-shaped  nucleus  (in  man)  ;  rela- 
tively large  spherules  in  protoplasm ;  highly  refractive ;  staining  deeply  with 
acid  aniliuo  dyes ;  abundant  in  cwlumic  lluid,  iu  serous  cavities,  in  inter 


79 


&> 


SYSTEM  OF  MEDICINE 


stices  of  areolar  tissue  (K  and  H),  and  in  bone  marrow  (Ehrlich)  ;  rare  in 
blood  (2-4  per  cent)  ;  amoeboid ;  non-phagocytic. 

Finely  Granular  Oxyphile.  —  Smaller  than  last  (in  man) ;  nucleus  branching  or 
polymerous,  staining  deeply ;  granules  very  small  and  spherical ;  feeble 
oxyphile  reaction  (Ehrlich's  amphophile  reaction  in  rabbit,  neutrophile  in 
man,  etc.).  Abundant  in  blood  (20-70  per  cent  of  all  leucocytes)  ;  absent 
from  ccBlomic  fluid ;  actively  amcaboid  and  phagocytic.  The  most  common 
form  of  pus  cell. 

Coarsely  Granular  Basophile.  —  When  found  free  in  coelomic  fluid,  round  nucleus 
staining  very  feebly ;  spherules  large  and  numerous,  stain  with  basic  dyes 
— somewhat  similar  cells  are  found  stationary  in  connective  tissue  spaces  — 
absent  from  human  blood  in  health  ;  non-phagocytic. 

Finely  GHranular  Basophile.  —  Spherical ;  smallest  of  the  wandering  cells ;  tri- 
lobed  nucleus ;  clear  cell  substance  containing  great  numbers  of  fine  baso- 
phile dots.  Found  in  human  blood  in  small  numbers  (1-5  per  cent)  ;  increased 
after  meals. 


From  this  description  of  the  character  of  the  various  forms  of  leuco- 
cytes (for  which  I  am  largely  indebted  to  Kanthack  and  Hardy)  it  will 
be  seen  that  certain  forms  are  characteristically  present  in  the  circulating 
blood,  namely,  the  finely  granular  oxyphile  and  the  finely  granular  baso- 
phile ;  others  in  the  body  fluid,  namely,  the  coarsely  granular  oxyphile 
and  coarsely  granular  basophile ;  while  the  lymphocytes  and  hyaline  cells 
are  common  to  both  fluids.  It  must  be  added  that  the  eosinophile,  or 
coarsely  grantdar  oxyphile,  are  also  present  in  small  numbers  in  the 
healthy  human  blood :  it  occurs  in  larger  numbers,  however,  in  diseased 
conditions  which  do  not  come  within  the  scope  of  this  article. 

Of  the  origin  and  relationship  of  these  diverse  cells  we  still  know 
very  little.  As  Gulland  has  pointed  out,  the  blood  of  the  embryo  is 
entirely  free  from  white  corpuscles.  The  exact  period  at  which  each 
form  makos  its  first  appearance  has  not  yet  been  studied,  although  in 
all  probability  such  a  study  would  throw  a  flood  of  light  upon  the  origin 
of  the  different  orders  of  cells. 

The  most  that  we  can  say  with  fair  certainty  is  that  the  lymphocytes, 
while  representing  the  larval  form  of  leucocytes  in  general,  are  in  the 
main  derived  from  lymphoid  tissue ;  that  some  of  them  develop  into  the 
hyaline  cells  (for,  as  Sherrington  and  others  have  noted,  every  gradation 
is  observable  between  these  two  forms) ;  and  that  what  appears  to  be  an 
immature  eosinophile  cell  can  often  be  detected  in  the  peritoneal  fluid, 
as  also  an  immature  coarsely  granular  basophile  cell  (Kanthack  and 
Hardy).  Beyond  this  we  have  not  at  present  advanced.*  Ehrlich's  sug- 
gestion that  the  eosinophile  cells  are  derived  from  the  bone  marrow  may 


II  quite  understand  that  sundry  obBGrv«.r8  rcKard  all  the  various  forms  of  leucocytes 
as  modiiications  one  of  another.  It  is  true  that  all  embryologically  have  the  same  origin ; 
BO,  for  example,  have  the  corpuscles  of  cartilage  and  bone,  yet  this  does  not  make  carti- 
lage and  bone  one  tissue.  Evcrard,  Gulland,  RutTor,  Dcmoor  and  Massart,  state  that  all 
transitions  are  observable  between  the  various  forms ;  I  cannot  but  think  that  the  methods 
of  staining  employed  by  these  observers  were  insulHciont  for  these  wide  conclusions.  It 
is  interesting  to  note  that  these  observers,  like  Kantliack  and  Hardy,  fouud  Ehrlich's 
«mphophilu  and  uoutrouhilu  colls  to  utaiu  with  oouiu,  i.e.  tc  bu  oxyphile. 


INFLAMMATION 


8i 


be  partially  true,  but  not  entirely ;  inasmuch  as  it  is  difficult  to  correlate 
the  preponderance  of  these  cells  in  the  body  fluid  with  so  special  and 
local  an  origin.  Nor  can  the  recent  observation  of  Siawcillo,  that 
eosinophile  cells  are  abundant  in  the  ray  which  possesses  neither  bone 
nor  bone  marrow,  be  regarded  as  favourable  to  Ehrlich's  hypothesis. 
And  again,  the  observations  of  MetschnikofE  and  his  pupils  render  it 
eminently  probable  that  some,  at  least,  of  the  large  hyaline  cells  are 
derived  not  from  lymphocytes,  but  from  proliferating  endothelial  cells 
of  the  lymph  and  blood-vessels  and  of  serous  surfaces.  Finally,  it  is 
noticeable  that  the  cells  with  multilobate  nucleus  (the  finely  granular 
oxyphile),  the  commonest  of  the  haemal  leucocytes,  are  not  to  be  recog- 
nised in  lymphoid  tissue :  yet,  as  Sherrington  has  pointed  out,  certain 
of  their  peculiarities,  notably  the  contorted  shape  of  the  nucleus,  may  be 
regarded  as  acquired,  inasmuch  as  if  they  be  allowed  to  remain  at  rest 
in  the  living  state  outside  the  body  the  nuclei  become  more  spherical. 

Of  these  varieties  of  wandering  cells  not  all  have,  so  far,  been  found 
to  bear  a  part  in  the  inflammatory  process :  but  certain  forms  appear  to 
have  distinct  functions  therein:  these  are  the  finely  granular  oxyphile 
(neutrophile),  the  coarsely  granular  oxyphile  (eosinophile),  and  the 
hyaline  cells.  » 

A  word  should  here  be  said  concerning  the  cells  of  later  development, 
appearing  as  a  result  of  inflammation  —  giant-cells,  Ranvier's  cells,  and 
Gluge's  corpuscles.  Of  these  the  last  are  evidently  leucocytes  of  the 
hyaline  type  which  have  taken  up  the  fatty  products  of  tissue  degeL  ora- 
tion; the  second — colossal  cells  breaking  down  with  great  ease — ar*i  of 
doubtful  origin.  Giant-cells  would  seem  to  be  of  more  than  one  variety : 
some  appear  to  be  due  to  aberrant  cell  growth,  wherein  the  nuclei 
undergo  division  without  the  protoplasm  of  the  cell  body  following  suit. 
The  characteristic  giant-cells  of  tuberculosis  and  chronic  inflammation 
may  now  be  said  with  fair  certainty  to  be  plasmodia,  in  all  respects  com- 
parable to  the  masses  of  fused  cells  seen  to  form  in  the  lower  animals 
around  foreign  bodies,  and  by  Kanthack  and  Hardy  around  masses  of 
bacteria  in  the  lymph  of  frogs  outside  the  body.  The  recent  observations 
of  Borel  and  of  Duenschmann  strongly  support  this  opinion. 

Phagocytosis. — In  the  case  of  a  very  large  number  of  pathogenic  micro- 
organisms (so  large  a  number  that  merely  to  enumerate  them,  with  the 
names  of  the  observers  and  of  the  animals  upon  which  the  observations 
have  been  conducted,  makes  a  list  so  long  that  in  the  bibliographical 
table  at  the  end  of  this  article  I  give  only  the  more  important  references, 
and  not  nearly  the  complete  list),  after  inoculation  into  the  organism, 
a  very  considerable  proportion  are  to  be  discovered,  sooner  or  later, 
within  wandering  cells  which  have  collected  in  the  region  of  inocula- 
tion. I  have  already  mentioned  more  than  one  case  of  this  nature  in 
discussing  the  comparative  pathology  of  inflammation.  Evidently  under 
certain  conditions  one  of  the  functions  of  certain  of  the  leucocytes  is  to 
attack  and  incorporate  bacteria.  The  leucocytes  having  these  properties 
are  more  especially  the  finely  granular  oxyphile  (where  the  injection  has 


VOL.    I 


G 


82 


SYSTEM  OF  MEDICINE 


been  into  a  neighbourhood  richly  supplied  with  vessels),  the  hyaline  cells 
chiefly  where  the  microbes  have  found  an  entry  into  the  body  cavity. 
It  is,  for  instance,  the  finely  granular  oxyphile  cell  which  is  found  in 
overwhelming  numbers  in  an  extending  subcutaneous  abscess,  and  these 
are  seen  to  contain  great  numbers  of  the  micrococci. 

The  conditions  leading  to  this  phagocytosis  have  been  very  fully 
worked  out  by  Metschnikoff.  He  has  amply  demonstrated  that  the 
microbes  can  be  taken  up  in  a  living  condition.  Thus,  if  the  Vibrio 
Metschnikovi  (a  form  closely  allied  to  the  cholera  spirillum)  be  inocu- 
lated into  the  anterior  chamber  of  the  eye  of  an  immunised  animal,  within 
a  very  few  hours  phagocytes  are  discovered  filled  with  the  small,  slightly 
curved  vibriones.     If  now  one  such  cell  be  isolated,  placed  in  a  drop  of 


a^' 


-a 


Vio.  1.  —  Resolution  of  acute  infectious  disease  (relapsinf?  fever),  spleen  pulp  of  monkey  (Macaous 
erytlir.),  showing  (")  mioropbogc,  inultinuclear,  witli  inceptod  spirochaetes ;  (b)  solitary,  and  (o) 
forininf?  dense  tangle,  (d  d)  nuclei  of  splenic  tissue  (Zeiss,  ■fg  ocular  4 ;  x  1515  diam.)-  —  [Motsch- 
nlkutr  (61).  ] 


broth  upon  a  coverslip,  made  into  a  hanging  drop  preparation  and  exam- 
ined under  the  microscope,  it  is  seen  that  the  broth  causes  the  death  of 
the  leucocyte;  while  with  time,  and  favourable  temperature,  the  microbes 
proliferate  rapidly,  and  completely  fill  the  corpuscle  until  it  disinte- 
grates; whereupon  they  proceed  to  multiply  in  the  surrounding  fluid. 
This  seizing  and  incorporation  of  microbes  does  not  then  necessarily 
lead  to  their  death.  In  certain  cases  of  acute  disease  there  may  be 
abundant  phagocytosis,  and  the  disease  progress  nevertheless;  the 
phagocytes  being  destroyed  by  the  products  of  the  incorporated  organ- 
isms. This  is  the  case  in  mouse  septicaemia,  in  swine  erysipelas,  and 
(as  has  been  shown  quite  recently  by  Gabritchewski)  in  diphtheria.  As 
M.  Koux  remarks :  "  lis  ont  fait  de  leur  mieux  en  englobant  les  microbes, 
mais  ceux-ci  se  sont  adaptes  au  milieu  iiiterieur  des  cellules,  et  ils  out 
triomphes."  * 

^Uuux.  —  Trans.  Internal.  Oongreaa  of  Hygiene,  Loudon,  1891,  ii.  p.  120. 


INFLAMMA  TION 


83 


In  other  less  acute  diseases,  such  as  gonorrhoea;  and  in  chronic 
maladies  of  a  tubercular  nature — in  tuberculosis,  leprosy,  and  glanders 
— the  bacilli  may  in  certain  stages  be  found  within  the  cells  and  rarely 
free  in  the  lymph  spaces,  they  appear  to  be  almost  parasitic,  after  the 
manner  of  the  microsphaera  previously  referred  to  as  infesting  the  amoeba. 


Fio.  2,— Two  giant-cells,  seen  nnder  high  magnification  (x  161B  dlam.)  from  a  rodent,  the  spermophllo, 
.   Inocnlated   with   tuberculosis,  to  show  stages  In  the  destruction  of  the  bacilli,     a,  unaltered 
bacillus ;  h,  bacillus  staining  badly,  and  with  greatly  thickened  capsule ;  c,  bacillus  granular  and 
breaking  up ;  <2 e,  " shadows."  —  [Metschnlkoff  (51).] 

In  these  cases  it  would  seem  as  though  the  toxic  properties  of  the 
microbes  and  the  antagonising  powers  of  the  cells  were  nearly  balanced. 
In  tuberculosis,  for  instance,  it  is  not  unusual  to  find  in  the  giant-cells 
some  bacilli  which  evidently  are  undergoing  degenerative  changes,  stain- 
ing poorly  and  irregularly,  or  but  faintly  traceable  as  unstained,  translu- 
cent shadows,  while  elsewhere  they  are  apparently  proliferating  despite 
their  intracellular  position.^  . 

1  It  is,  however,  unsafe  to  declare  in  all  cases  that  because  a  micro-organism  con- 
tinues to  stain  well  therefore  it  was  living  at  the  moment  the  preparation  was  taken  and 


SYSTEM  OF  MEDICINE 


And  this  equality,  or  almost  equality  of  the  resisting  powers  of  cells 
and  microbes,  may  explain  the  chronic  nature  of  the  diseases  above  men- 
tioned. Nevertheless,  in  general,  it 
may  be  stated  that  there  is  some  rela- 
tionship to  be  recognised  between  tlie 
amount  of  phagocytosis  and  the  viru- 
lence of  the  microbe ;  the  more  virulent 
the  microbes  the  less  the  proportion  of 
them  taken  up  by  the  cells ;  and,  as 
Kanthack  and  Hardy  have  pointed  out, 
the  longer  the  time  before  the  phago- 
cytes come  into  action.  As  is  the  case 
in  the  unicellular  organisms,  so  in  the 
wandering  cells  of  higher  animals  the 
process  of  destruction  of  the  included 
microbes  can,  under  suitable  condi- 
tions, be  seen  to  be  digestive.  Sev- 
eral observers  have  seen  the  anthrax 
bacillus,  in  frogs  and  other  animals, 
wholly  or  in  part  surrounded  by  a 
vacuole  developed  within  the  leucocyte ;  and,  as  an  evident  result,  the 


Vw.  8.  —  Phogocytos,  mocrophof^e  and  mlcro- 

Jilm^o,  to  shuw  HtitKus  of  di^eBttoii  and 
testriiction  of  bncllH,  from  splcun  and  evo 
respectively  of  wldto  rat  wltli  anthrax.  In 
i,  part  of  the  bauillim  is  uiiatfcvtod,  Iiiit  a 
viicnolo  lias  forii>  *d  around  the  otlier  part, 
wliicli  ftirthor  lias  now  lost  the  power  of 
talcing  tho  stain.  In  S,  various  stages  tro 
seen,  tho  bacilli  passing  through  the  granu- 
lar badly  staining,  to  tho  vacuolated  un- 
stained, until  flnully  but  tcAwt  "  shadows  " 
ore  observable  (Zeiss  A,  oo.  8).  —  [Metsch- 
nlkotl(51).] 


Fio.  4. —Anthrax  of  pigeon  (an  animal  but  slightly  misceptiblo  to  tho  diseaso)  to  show  stogoB  of 
destruction  of  bacilli  by  phagocytes.  1  and  2,  macrophages :  1,  from  exudation  from  eye  of  re- 
froctory  bird  ;  2,  ft-om  muscle  of  region  of  inoculation  of  bird  that  buccuuiImmI  ;  3,  A,  5,  micro- 
nhages  —all  from  eye  twenty-seven  hours  after  in(H!ulation ;  a  a,  unaltered  bacilli;  &•  //'  b*,  bacilli 
becoming  more  and  more  degenerated  and  indistinct:  o  c,  d6brls  of  bacilli  (Zeiss  A,  ooulur  3).— 
[Met8chnlkoir(51).] 

portion  so  surrounded  has  been  seen  to  become  swollen  and  fainter  when 
stained,  until  it  has  undergone  a  veritable  digestion  and  dissolution. 
As  with  the  lower  organisms,   so  with  the  wandering  cells    of 


fixed  by  heat.  Tims  in  pneumonia  after  tlie  crisis  a  fair  number  of  diplococci  may  bo 
found  Avithin  the  leucocytes  of  tho  expectorated  contents  of  the  alveoli,  and  these  may 
stain  perfectly  well ;  yet  it  may  bo  impossible  to  gain  a  single  growth  of  tho  diplocovcus 
from  tho  same  material. 


INFLAMMA  TION 


8S 


the  higher,  there  is  an  evident  attraction,  or  chemiotaxis,  whereby 
these  cells  pass  towards  the  microbes  and  their  products;  and  this 
chemiotaxis  would  also  seem  in  general  to  be  in  the  inverse  ratio  of 
the  virulence  of  tlie  microbes.  I  say  in  general,-  for  with  chemiotaxis  as 
with  phagocytosis  there  appear  to  be  exceptions  to  any  uniform  law;  and 
cases  can  be  brought  forward — of  diphtheria,  for  example — in  which  the 
leucocytes,  instead  of  being  repelled,  are  attracted  in  great  numbers  to 
the  region  of  inoculation  of  a  most  virulent  bacillus. 

The  chemiotactic  properties  of  the  wandering  cells  have  been 
especially  studied  by  Pekelharing,  Leber,  Massart  and  Bordet,  and  by 
Gabritchewski. 

Of  the  results  obtained  by  these  observers  the  most  important  are 
that  leucocytes  are  variously  attracted  towards  various  substances.  Thus 
Leber  found  that  the  introduction  into  the  system  of  finely-powdered 
copper  and  various  compounds  of  mercury  caused  an  abundant  collection 
of  the  wandering  cells  around  the  particles,  while  powdered  gold,  silver 
and  iron  exerted  no  such  attraction.  Gabritchewski  and  A.  Schmidt 
showed  that  the  products  of  bacterial  growth  in  general  possessed  chemio- 
tactic properties  yet  more  powerful  than  simple  chemical  compounds. 
While  the  degrco  of  positive  chemiotaxis  is  found  to  vary  within  wide 
limits,  the  examples  brought  forward  of  negative  chemiotaxis  exerted  by 
bacterial  products  have  so  far  been  very  few  —  so  few  as  to  support  the 
contention  of  Dr.  Kanthack,  that  it  is  very  doubtful  whether  any  microbes 
by  their  products  actually  repel  the  leucocytes,  though  they  are  capable 
of  causing  the  rapid  destruction  of  the  attracted  leucocytes,  and  so  of 
rendering  the  area  around  the  microbes  relatively  free  from  wandering 
cells. 

A  very  good  study  of  the  action  of  bacteria  of  different  degrees  of 
virulence  can  be  made  by  repeating  an  experiment  of  Metschnikoff.  The 
rabbit  is  an  animal  susceptible  to  the  growth  within  its  tissues  of  the 
bacillus  of  anthrax.  As  is  well  known,  there  are  various  means  whereby 
the  virulence  of  this  microbe  can  be  diminished ;  so  that  if  cultures  of 
the  "attenuated"  bacillus  be  inoculated  into  susceptible  animals,  these, 
instead  of  causing  a  fatal  disease,  induce  but  a  transient  local  inflam- 
matory disturbance,  accompanied  by  fever,  and  followed  by  complete 
recovery.  If  now  a  small  quantity  of  a  virulent  culture  of  the  bacillus 
be  inoculated  into  the  one  ear  of  a  rabbit,  and  an  equal  quantity  of  an 
attenuated  culture  into  the  other,  the  results  are  very  instructive. 
Within  twenty-four  hours  it  can  bo  noticed  that  an  acute  inflammation 
has  been  induced  in  both  ears ;  in  both  the  vessels  round  the  seat  of 
inoculation  are  greatly  congested,  but  whereas  at  the  seat  of  inoculation 
of  the  virulent  organism  there  is  a  serous  inflammation  so  intense  that 
the  skin  is  raised  and  separated  from  the  subjacent  tissues  by  a  clear, 
transparent,  reddish  fluid  which  also  infiltrates  the  decj)er  tissues,  in 
the  other  ear  there  is  not  nearly  the  same  amount  of  swelling  and  serous 
exudation;  the  region  of  inoculation  is  more  opafjue  and  solid.  Upon 
mure  minute  examiuutiuu  the  serous  fluid  iu  the  first  uui-  is  fouud  to 


85 


86 


SYSTEM  OF  MEDICINE 


contain  relatively  very  few  leucocytes ;  the  firmer  mass  in  the  second  is 
composed  of  a  huge  aggregation  of  leucocytes  [yid.  art.  "  Anthrax  "]. 

Evidently,  therefore,  the  relative  number  of  leucocytes  migrating, 
and  the  quantity  of  serum  exuded,  depend  very  largely  upon  the  inten- 
sity of  the  irritant;  and  by  the  intensity  of  the  irritant,  and  the 
behaviour  of  the  leucocytes,  the  forms  of  the  inflammatory  process  may 
be  classified. 

But  to  the  subject  of  classification  I  shall  refer  later.  In  the  meantime 
it  is  well  to  sum  up  the  theory  of  phagocytosis  as  upheld  by  Metsch- 
nikoff  and  those  who  see  in  this  phenomenon  the  all-important  factor  in 
inflammation  and  the  repair  of  injury  (as  also  in  the  production  of 
immunity),  in  order  that,  having  put  clearly  forward  the  tenets  of  those 
upholding  the  theory,  I  may  the  more  readily  state  wherein  lies  the 
strength  and  wherein  the  weakness  of  the  doctrine. 

The  theory  of  phagocytosis  as  set  forth  in  MetschnikofiE's  later  writings 
may  be  summed  up  in  the  following  theses :  — 

1.  That  certain  of  the  leucocytes  present  in  the  blood  and  lymph, 
notably  the  finer  granular  oxyphile  or  neutrophile,  and  the  large 
hyaline,  are  capable  under  certain  conditions  of  taking  up  bacteria  which 
have  gained  entry  into  the  system. 

2.  That  in  addition  to  these  the  splenic  corpuscles,  the  cells  form- 
ing the  endothelium  of  capillaries,  and  sundry  other  fixed  cells  of  meso- 
blastic  origin,  possess  the  same  property,  although  they  exert  it  to  a  less 
extent. 

3.  That  these  phagocytes  seize  upon  and  destroy  living  and  active 
microbes  under  certain  conditions. 

4.  That  the  more  virulent  the  microbe  the  less  the  tendency  for  the 
leucocytes  above  mentioned,  and  for  the  other  fixed  cells,  to  take  up  the 
bacteria.  The  less  virulent  the  microbe  the  more  extensive  the  phago- 
cytosis. 

5.  That  in  addition  to  this  power  on  the  part  of  certain  cells  (the 
phagocytes)  to  take  up  and  destroy  certain  bacteria,  another  factor 
has  to  be  called  in  to  explain  why  the  wandering  cells  of  the  body 
migrate  towards  the  focus  or  foci  where  the  micro-organisms  have 
gained  an  entry  into  the  body.  This  factor  is  the  "cliemiotaxis" 
exerted  by  the  products  of  bacterial  growth,  and  by  some  other  substances, 
Hiicli,  for  example,  as  the  productsof  dcatli  of  tissue  and  of  wanderingcolls ; 
and  experimentally  also  certain  chemical  irritants  as,  for  example,  turpen- 
tine and  mercury.  In  the  case  of  the  virulent  microl)es  the  leucocytes 
are  not  attracted  to  the  focus  of  infection.  There  is  a  "negative" 
chomiotaxis,  and  thus,  in  the  absence  of  j)hagocytosi8,  the  i)roliforation  of 
the  microl)es  takes  ))la('.e  without  hindrance;  whereas  the  loss  virulent 
microbes  and  their  ])roduct8  attract  the  leucocytes,  they  exert  a  positive 
cliemiotaxis,  so  that  there  is  a  migration  of  leucocytes  through  tlie 
capillary  and  venous  walls  to  the  fotuis  of  infection,  and  the  leucocytes 
taking  up  the  microbes  tend  to  arrest  the  infective  process. 

(5.   That  the   leucocytes   may  become  acciustomed   and  eventually 


w  n 


n  \ 


INFLAMMA  TION 


87 


attracted  to  substances  from  which  at  first  they  were  repelled,  and  thus 
a  negative  may  be  transformed  into  a  positive  chemiotaxis. 

7.  That  the  cells,  having  once  acquired  positive  chemiotactic  pro- 
perties in  relation  to  the  products  of  any  specific  microbe,  retain  and 
transmit  these  properties  through  a  series  of  cell  generations,  the  length 
of  which  varies  according  to  the  microbe,  the  extent  of  the  primary 
reaction,  and  the  idiosyncrasies  of  the  individual. 

8.  That,  consequently,  the  cure  of  zymotic  or  mycotic  disease, 
whether  localised  or  general,  and  immunity  also,  are  mainly  brought 
about  by  the  activity  of  special  cells  (the  phagocytes),  and  are  prima- 
rily dependent  upon  the  attraction  existing  between  these  cells  and  the 
products  of  bacterial  metabolism. 

9.  The  process  of  inflammation  is  essentially  the  endeavour  on  the 
part  of  the  organism  to  promote  the  migration  of  leucocytes,  and  to 
aid  the  inclusion  and  destruction  of  the  irritant.  "The  essential  and 
primordial  element  of  a  typical  inflammation  is  a  reaction  of  phagocytes 
against  the  irritant  (agent  nuisible)."  (14)  Or,  more  fully,  "  inflamma- 
tion is  to  be  regarded,  on  the  whole,  as  a  phagocytic  reaction  of  the 
organism  against  irritants,  —  a  reaction  which  at  times  is  accomplished 
by  the  wandering  cells  alone,  at  times  with  the  aid  of  the  vascular 
(fixed)  phagocytes,  or  with  that  of  the  nervous  system." 

10.  That  in  rare  cases  bacteria  may  be  affected  if  not  destroyed 
by  extracellular  action,  by  substances  derived  from  the  leucocytes  and 
dissolved  in  the  surrounding  lymph. 

In  the  terms  of  this  theory,  then,  phagocytosis  is  the  all-important 
factor  in  the  inflammatory  i)rocess,  the  vascular,  exudative,  nervous  and 
other  phenomena  being  auxiliary  means  whereby  the  phagocytic  pro- 
perties of  the  wandering  and  fixed  mesodermal  cells  may  be  brought 
more  fully  into  action:  the  determination  of  leucocytes  that  I  have 
described  is  almost  entirely  to  be  attributed  to  an  endeavour  on  the 
part  of  these  cells  to  take  up  and  destroy  the  irritant. 

It  is  necessary  now  to  ask  to  what  extent  this  doctrine  is  to  bo 
accepted.  Certainly  phagocytosis  is  a  factor  in  the  inflammatory  pro- 
cess—  no  antagonist  of  this  doctrine  nowadays  is  prepared  to  deny 
this  —  but  does  it  occupy  the  all-imitortant  position  arrogated  to  ifc 
by  Metschnikoff  ?  Metschnikoff  himself  admits  tliat  there  are  certain 
wandering  cells  —  the  coarsely  granular  oxyphiles — which  never  act  as 
phagocytes.  When  powers  so  great  are  found  to  belong  to  one  set  of 
leucocytes,  is  it  likely  that  another  sot,  which  is  also  C8i)0cially  attracted 
to  the  inflammntory  focnis,  is  absolutely  devoir  of  either  ba(!tericidal  or 
antitoxic  function?  Or,  to  approach  the  matter  from  another  stand- 
point, let  us  take  a  case  su|)plied  recently  by  (labritchowski  from 
Metschnikoff 8  laboratory.  If  a  guineorpig  Iw  rendered  refractory  to 
the  bacillus  of  diphtheria,  and  if  the  vulva  be  cauterised  aiul  infected  by 
a  virulent  culture  of  tliis  bfieillus,  there  vosiilts  a  necrosis  of  tlio  surface 
layers.  On  the  free  surface  of  the  necrosed  region  lie  the  j)rolifcrating 
microl)os;  apposed  to  the  uiulcr  surftwie  of  the  necrosed  area  is  a  hirgo 


88 


SYSTEAf  OF  MEDICINE 


collection  of  migrated  leucocytes.  In  about  three  days  the  necrosed 
tissue  sloughs  off,  and  recovery  and  repair  ensue.  But  in  this  process 
little  phagocytosis  is  observable.  The  phagocytosis  is  evidently  not 
commensurate  with  the  extent  of  the  inflammation ;  and  if,  as  Metschni- 
kotf  urges,  the  leucocytes  are  the  all-important  factor,  their  powers  of 
defence  must  here  include  something  beyond  the  incorporation  of  the 
micro-organisms.  The  same  additional  something  would  seem  to  be 
wanted  to  explain  the  healing  of  abscesses. 

A  crucial  test  of  the  importance  of  phagocytosis  has  been  devised  by 
Baumgarteu,  and  repeated,  with  like  results,  by  Sanarelli.  If  microbes 
be  placed  in  an  animal  which  has  normally  the  power  of  withstanding 
the  growth  of  such  microbes;  and  if,  further,  they  be  so  placed  (in 
bags  of  filter  paper,  celloidin,  or  pith)  that  the  leucocytes  cannot  attack 
them,  although  the  body  fluids  can  easily  bathe  them,  then,  if  Metschni- 
koff  bo  right,  the  microbes  ought  to  flourish  unatt'ected.  liaumgarten 
and  Sanarelli  found  that  this  is  not  so,  that  the  microbes  are  destroyed 
despite  the  absence  of  phagocytes ;  but  Metschnikoff,  repeating  these 
experiments,  obtained  diametrically  opposite  results,  lioth  Baumgarten 
and  Sanarelli  are  capable  observers  jtlthough  it  is  true  that  the  former 
by  the  very  violence  of  his  attack  upon  Metschnikoff  has  materially 
weakened  his  position.  It  is,  however,  ditticult  to  explain  away  their 
positive  results,  or  to  arrive  at  a  conclusion  other  than  that  under  certain 
conditions  the  microbes  may  bo  destroyed  without  being  ingested. 

Tlie  Humoral  Theory.  —  The  conception  that  there  is  some  agency 
besides  phagocytosis  pure  and  simple  has  led  bacteriologists,  in  the 
study  of  phenomena  of  inflammation  and  immunity,  to  engage  in  a  very 
remarkable  series  of  experiments.  Altlumgh  some  of  them  have  failed 
to  establish  a  satisf.octory  theory  of  immunity,  they  have  led  to  results 
of  such  high  importance  as  the  discovery  of  the  serum  treatment  of 
diphtheria  and  tetanus.  The  majority  of  tl'  "e  researches,  indeed, 
bear  especially  upon  the  production  of  immunity,  and  only  secondarily 
upon  the  inflammatory  process.  It  is  unnecessary  for  me,  therefore,  to 
describe  them  in  detail ;  it  will  suffice  if  I  indicate  the  direction  taken 
by  the  more  important  among  them. 

First  in  order  of  time  may  bo  mentioned  Nuttall's  observations. 
In  an  attempt  to  repeat  Metschnikoff's  researches  upon  the  destruc- 
tion of  the  anthrax  bacillus,  this  observer  noticed  that  if  ho  placed 
a  fine  canula  containing  a  fresh  culture  of  attenuated  anthrax  bacilli  in 
the  tissue  of  a  rabbit's  oar,  there  resulted  in  sixteen  hours  a  rich  cellular 
exudation;  but  phagocytosis  appeared  not  to  reach  its  maximum  for 
twenty-two  hourfl,  and  even  then  half  of  the  bacilli  lay  free  and  not  taken 
up  by  cells;  and  ho  found,  further,  that  tho  free  bacilli  showed  involu- 
tion and  degeneration  to  the  same  extent  as  aid  the  ingested.  Tliis  led 
hiui  to  stiuly  the  (effect  of  blood  serum,  deflbrinated  ])lood  and  lym])h  upon 
the  bacilli,  and  he  discovered  that  those  fluids  had  a  remarkably  rajiid 
action,  destroying  great  numbers  within  a  vc^ry  few  hours.  Moritz, 
Tratibe,  Von  Kodor  and  others,  had  previously  recognised  this  rapid 


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IN  FLAM  MA  TION 


89 


destruction  of  microorganisms  in  the  living  blood,  but  Nuttall's  very 
full  research  appeai-ed  to  show  conclusively  that  the  bacteria-destroying 
power  resided  largely  in  the  serum,  and  that  in  inflammation  the  exuded 
fluid  rather  than  the  leucocytes  brought  about  the  destruction  of  the 
microbes. 

These  observations  were  confirmed  and  extended  by  Nissen,  Behring, 
and  Buchner,  and  a  most  valuable  series  of  contributions  (see  article  on 
the  "General  Pathology  of  Infection")  have  been  made  by  Hankin, 
Buchner,  Vaughan,  Tizzoni  and  Cattani,  Behring,  and  others,  upon  the 
nature  and  properties  of  the  substances  to  be  derived  from  the  blood 
serum  of  animals  either  naturally  immime  to  certain  diseases,  or  rendered 
immune  by  one  or  other  procedure.  What  is  more,  it  has  been  rec- 
ognised that  two  orders  of  substances  are  recognisable:  one  capable 
of  destroying  pathogenetic  microbes,  the  other  not  destroying  them,  but 
rendering  their  products  inert. 

It  would  thus  at  first  sight  appear  that  in  these  discoveries  there  is  a 
direct  contradiction  to  the  theory  of  phagocytosis.  Yet  upon  further 
study  this  is  found  not  to  be  the  case. 

As  was  shown  by  Nuttall,  at  the  commencement  of  these  studies,  the 
blood  serum  removed  from  the  body  acts  far  more  rapidly  and  energeti- 
cally than  do  the  blood  plasma  and  lymph  within  the  bddy.  The  dis- 
parity of  action  between  the  two  is  remarkable.  Thus  Lubarsch  has 
shown  that  in  order  to  kill  a  rabbit  by  anthrax,  by  injection  into  the 
circulating  blood,  at  least  10,000  virulent  bacilli  of  the  disease  must  be 
introduced:  a  smaller  number  produces  only  a  transient  disturbance. 
That  is  to  say,  the  whole  circulating  blood  can  only  destroy  less  than 
1C,000  bacilli  at  a  time.  On  the  other  hand,  one  cubic  centimeter  (15 
minims)  of  rabbit's  blood  serum  can  in  a  few  minutes  kill  an  equal  or 
even  greater  number. 

27te  Cellulo-Humoral  Tfieorif.  —  If  the  serum  and  if  the  blood  plasma 
contain  bactericidal  substances,  these  must  in  all  likelihood  be  developed 
by  certain  cells,  and  thus  at  b  ttom  tlio  humoral  theory  must  be  cellular; 
and  the  very  fact  of  the  great  increase  in  the  bactericidal  properties 
of  the  blood  immediately  on  its  withdrawal  from  the  body,  must  suggest 
that  in  the  changes  which  occur  in  the  extravascular  blood  there  is  a 
liberation  and  solution  of  bactericidal  substances.  Now  the  first  and 
foremost  of  these  changes  is  the  breaking  down  of  the  leucocytes 
as  the  blood  begins  to  clot.  It  may  therefore  be  that  this  breaking 
down  of  the  leucocytes,  with  liberation  of  tlieir  conteuts,  is  capable  of 
explaining  the  increased  bactericidal  action  of  defibrinated  blood  and 
blood  serum. 

That  the  leucocytes  contain  bactericidal  substances  was  first  demon- 
strated by  Dr.  Hankin,  who  obtained  from  the  lymy'^mtic  glands  and 
spleens  of  animals  immune  to  antlirax  (flogs  and  cats),  a  proteid  of  tlio 
nature  of  a  globulin  identical  with  Dr.  Halliburton's  cell  globulin  /8,  and 
having  a  bacteria-killing  power  similar  to  that  iiosseasod  by  blood  serum. 
In  later  observations  upon  the  rat  he  showed  that  there  was  a  relationship 


89 


90 


SYSTEM  OF  MEDICINE 


between  the  amount  and  activity  of  these  "  defensive  proteids  "  and  the 
power  of  resistance  of  the  animal  to  the  disease.  Thus  Hankin  showed 
that  in  animals  possessing  the  power  of  destroying  bacilli,  the  organs 
containing  the  largest  collections  of  leucocytes  yielded  notable  quantities 
of  a  bacteriardestroying  substance. 

For  the  last  few  years  I  have  steadily  urged  this  view,  and  observa- 
tion after  observation  is  proving  it  to  be  correct.  Recently  Buchner  has 
shown  that  if  sterilised  emulsions  of  the  gluten  of  wheat  be  injected  into 
the  pleural  cavity  of  a  dog  and  rabbit,  its  presence  leads  to  the  pouring 
out  of  an  aseptic  exudation  peculiarly  rich  in  leucocytes,  and  this  exudor 
tion  is  more  bactericidal  than  is  the  blood  and  serum  of  the  animal. 
Further,  Victor  C.  Vaughan  is  led  to  the  conclusion  that  the  bactericidal 
action  is  associated  with  the  leucocytes  by  his  discovery  that  from 
blood  serum  a  nuclein  (or  nucleinic  acid)  can  be  separated — a  body,  that 
is,  which  so  far  has  been  found  exclusively  in  connection  with  nucleated 
cells.  This  nuclein  is  either  itself  bactericidal,  or  has  a  bactericidal 
substance  in  intimate  association  with  it ;  and  Vaughan's  observations 
and  conclusions  have  been  substantiated  by  the  later  and  independent 
researches  of  Kossel  upon  nucleinic  acid. 

Further  confirmation  of  the  correctness  of  these  views  —  that  the 
bactericidal  action  of  the  blood  serum  is  due  to  the  breaking  down  of  the 
leucocytes — has  been  supplied  from  the  laboratory  of  Denys  at  Louvain. 
Denys  and  Havel  have  shown  that  the  blood  and  exudations  of  the  dog, 
freed  from  leucocytes  either  by  filtration  or  by  centrifugal  action,  lose 
their  bactericidal  action,  regaining  it  when  the  leucocytes  are  reintro- 
duced. Van  der  Velde  induced  an  exudation  rich  in  leucocytes  by 
injecting  into  the  pleural  cavities  of  rabbits  sterilised  cultures  of  the 
pyococci,  and  killing  the  animals  at  various  periods.  Centrifugalising 
the  pleural  fluid,  he  found  that  the  older  the  exudation,  and  the  richer  it 
had  boon  in  wandering  cells,  the  more  powerful  its  bactericidal  action, — 
this  being  out  of  all  proportion  to  the  bactericidal  action  of  the  blood 
serum  removed  at  the  same  time  and  similarly  centrifugalised. 

liut  more  convincing  proof  has  been  gained  by  a  study  of  the  leuco- 
cytes in  action.  Even  in  1887  Ribbert,  in  his  studies  upon  the  fate 
of  spores  of  various  species  of  aspergillus  and  mucor  inoculated  into  the 
anterior  chamber  of  the  rabbit's  eye,  had  found  that  two  stages  of  reaction 
were  recognisable :  at  first  the  spores  and  developing  hyphal  filaments 
became  surrounded  by  dense  clusters  of  leucocytes,  which  renuiinod  in 
apposition  to,  but  did  not  ingest  the  micro-organisms.  Nevertheless 
they  appeared  to  bring  about  a  weakening  and  lowering  of  vitality  on 
the  part  of  the  spores  and  filaments,  so  that  after  a  time  other  cells 
could  manifest  their  phagocytic  activity  and  take  them  up.  llibliert,  it 
is  true,  attributed  the  lowering  of  vitality  to  the  walling  in  ('*  Wallbil- 
dung")  by  the  leucocytes,  and  consecpicnt  lack  of  nutrition ;  but  the  fact 
remains  that  he  demonstrated  a  preparatory  extracellular  action  upon 
the  micro-organisms  by  the  leucocytes. 

Altogether  the  fullest  and  most  imi)ortant  studios  upon  this  extra- 


i|ll£ 


INFLAMMA  TION 


91 


,■'1 
\\'i 


cellular  action  have  been  those  of  Kanthack  and  Hardy.  In  their  first 
communication  to  the  Royal  Society  these  observers  showed  (and  their 
experiment  can  be  repeated  without  diinculty)  that  if  a  drop  of  frog's 
lymph  be  placed  upon  a  coverslip,  with  the  addition  of  a  few  anthrax 
bacilli,  and  this  preparation  be  suspended  in  a  moist  chamber,  an  ex- 
amination extending  over  four  or  five  hours  reveals  the  following  suc- 
cession of  changes : — 

1.  The  coarsely  granular  oxyphile  cells  are  strongly  attracted  to  the 
bacilli :  they  move  towards  them,  and  apply  themselves  to  their  surface ; 
their  protoplasm,  ordinarily  sluggish,  exhibits  quick  streaming  move- 
ments. Next  the  eosinophile  granules  are  discharged,  and  the  bacilli 
begin  to  show  signs  of  degeneration.  During  this  stage  the  hyaline 
cells,  the  phagocytes  proper,  remain  quiescent,  and  are  not  even  at- 
tracted towards  the  bacilli. 

2.  The  hyaline  cells  proliferate  and  eventually  approach  the  masses 
of  oxyphile  cells  surrounding  the  bacilli;  they  fuse  with  these — forming 
a  Plasmodium  around  the  chains  —  and  for  the  next  hour  or  two  nothing 
can  be  clearly  made  out  as  to  the  action  of  individual  cells. 

3.  The  first  stage  in  the  dissolution  of  the  mass  is  the  separation 
and  wandering  away  of  the  oxyphile  cells ;  next,  the  hyadiue  phagocytes 
containing  remnants  of  the  bacilli  within  vacuoles  slowly  break  apart. 

4.  A  third  set  of  cells,  with  basophile  granules,  is  observed  to 
approach  during  this  last  period;  as  to  their  functions  Kanthack 
and  Hardy  are  a  little  doubtful. 

Here,  then,  we  have  clear  evidence  of  division  of  labour  among  the 
wandering  cells  of  the  frog :  the  coarsely  granular  oxyphile  cells  act  as 
unicellular  glands  discharging  or  excreting  their  granules,  and  these 
granules  dissolving  appear  to  exert  a  deleterious  action  upon  the  bacilli, 
in  consequence  of  which  the  hyaline  cells  are  now  capable  of  ingesting 
them.  I  may  add  that  occasionally  the  coarsely  granular  cells  may  bo 
seen  to  act  when  not  in  immediate  apposition  to  the  microbes ;  the  num- 
ber of  granules  in  a  cell  may  diminish,  and  at  th  o  same  time  neighbour- 
ing bacilli  manifest  signs  of  partial  dissolution.^ 

Continuing  their  research  Kanthack  and  Hardy  have  demonstrated 
these  distinctions  in  the  function  of  the  different  forms  of  leucocytes 
throughout  the  vertebrata  up  to  man.  They  have  shown  that  in  general 
the  hyaline  cells  act  as  the  phagocytes  of  the  lymphatic  and  cffilomic 
system ;  the  finely  granular  oxyphile  (neutrophile  and  amphophile)  as 
the  phagocytes  of  the  haemal  system;  while  the  coarsely  granular 
oxypliilo  (eosinophile)  when  present  possess  excretory  functions. 

if  capillary  chambers  filled  with  bacilli  or  their  products,  or  some 
irritant  such  as  nitrate  of  silver  or  turpentine,  were  placed  under  the 
skin,  or  in  the  peritoneal  cavity,  and  allowed  to  remain  there  for  periods 

1  Mesnil,  in  a  long  and  often  suRKostive  work,  which  apponrod  wliilo  thiH  article  waa 
in  tlio  proHH,  contradictH  those  obsorvatinnH  of  Kanthaclc  and  Iliirdy.  Appiintiitly  lin 
novor  once  attempted  to  repeat  their  prncodiiro,  never  onco  attempted  tlie  Hlmple  metliods 
I  ocossary  to  contirui  their  results.    His  oritiuiRni  must  titorofore  bo  relatively  valueless. 


91 


92 


SYSTEM  OF  MEDICINE 


up  to  twenty-four  hours,  they  were  found  to  contain  a  multitude  of  cells, 
chiefly  of  the  coelomic  type.  ]  f  the  irritant  were  situated  in  such  a 
position  as  to  appeal  to  the  bloo  1-vessels  of  a  vascular  membrane  rather 
than  to  the  cells  of  the  connectiv  e  tissue  spaces,  then  the  cells  were  those 
of  the  haemal  system.  In  both  cases  in  the  earliest  stages  there  was 
usually  found  a  preponderance  of  the  coarsely  granular  oxyphile  cells. 
Even  in  cutaneous  blisters  induced  upon  themselves,  while  the  main  mass 
of  cells  present  in  the  serous  exudation  were  the  finely  granular  oxyphile 
of  haemal  origin,  the  coarsely  granular  were  always  more  abundant  rela- 
tively to  the  others  than  in  the  blood.  The  rate  of  accumulation  was 
found  to  vary  according  to  the  irritant.  Thus,  comparing  the  action  of 
the  virulent  B.  anthracis  and  the  harmless  B.  ramosus  upon  rabbits  and 
guinea-pigs,  it  was  seen  that  if  cultures  of  these  two  forms  were  placed 
within  capillary  tubes  and  introduced  into  the  peritoneal  cavity,  with  the 
former  only  the  coarsely  granular  oxyphile  found  its  way  into  the  tubes 
(even  after  seven  hours) ;  whereas  with  the  latter  enormous  numbers  of 
the  hyaline  phagocytes  had  invaded  the  chambers  within  two  and  a  half 
hours.  In  the  former  case  also  the  total  number  of  invading  cells  of  all 
kinds  was  very  much  less  than  in  the  latter  case ;  and  there  was  clear 
evidence  of  the  abundant  disintegration  and  dissolution  of  many  of  the 
cells.  This  destruction  of  a  certain  number  of  cells  occurred,  whatever 
the  nature  of  the  microbe  introduced  into  the  system ;  and,  as  these 
observers  point  out,  it  must  profoundly  alter  the  chemical  constitution 
of  the  plasma,  and  may  therefore  play  an  important  part  in  the  struggle 
with  the  bacilli.  They  obsei  ved  phenomena  of  the  same  nature  as  those 
of  the  frog's  lymph,  when  they  placed  anthrax  bacilli  in  han":ing  drops 
of  human  blister  fluid  and  examined  the  preparations  upon  the  warm 
stage,  noticing  here  also  the  rapid  diminution  of  the  granules  of  the 
eosinophilo  cells. 

Finally,  it  must  be  added  that  MetschnikofE  (while  misunderstanding 
wholly  the  drift  of  these  last-mentioned  researches)  has  recently  admitted 
that  the  wandering  cells  are  capable  of  exerting  an  extracellular  activity 
upon  the  bacteria.  Certain  observations  of  R.  Pfeiffer  had  revealed  that, 
under  certain  conditions,  when  guinea-pigs  have  been  rendered  highly 
refractory  to  the  spirillum  of  cholera,  these  microbes  when  injected  into 
the  peritoneal  cavity  are  rapidly  modified,  becoming  swollen  and  spheri- 
cal before  any  phagocytosis  has  time  to  come  into  play ;  and  this  alteration 
was  explained  by  Pfeiffer  as  due  to  the  fluid  secreted  by  the  peritoneal 
cells  following  upon  the  inoculation.  Without  detailing  MetschnikofE's 
criticism  of  the  value  of  these  observations,  it  will  suffice  to  say  that, 
carefully  repeating  them,  he  discovered  that  five  minutes  after  such 
injection  the  leucocytes  in  the  peritoneal  fluid  —  "  polynucloar,"  mononu- 
clear, and  cosinopliilous  —  were  surrounded  by  a  layer  of  spirilla,  while 
the  lymphocytes  and  red  corpuscles  were  entirely  free  from  any  such 
surrounding.  Here  in  the  immediate  neighbourhood  of  the  wandering 
cells,  the  short,  curved  bacillary  forms  could  be  seen  to  have  undergone 
the  transformation  into  globules.   Motschnikoff  further  recognised  a  clear 


INFLAMMA  TION 


93 


zone,  evidently  of  exuded  liquid,  between  the  leucocytes  and  the  spirilla. 
Whether  this  be  a  true  secretion,  or  an  accompaniment  of  the  death  of 
the  cells,  he  is  not  at  present  prepared  to  say. 

In  this  way  Metschnikoif  admits  that,  besides  phagocytosis,  an  extra- 
cellular action  of  the  wandering  cells  does  occur ;  so  that  now  the  only 
point  of  paramount  importance  to  be  agreed  upon  is  the  extent  to  which 
the  extracellular  activity  is  manifested  intra  vitam.  Metschnikoff  at 
present  holds  that  h  plays  a  very  secondary  part  compared  with  phago- 
cytosis ;  others,  like  Buchner  in  Germany,  Denys  in  Belgium,  Kanthack 
and  Hardy  in  England,  hold  that  its  part  is  of  high  importance.  Person- 
ally, while  holding  that  phagocytosis  has  been  conclusively  proved  to  be 
of  singularlv  bigh  importance,  I  cannot  but  see  in  this  extracellular  action 
of  acti\  e  and  of  disintegrating  leucocytes  an  adjuvant  to  the  former  factor, 
and  one  which  under  certain  conditions  is  even  of  greater  value  to  the 
organism  in  its  attempt  to  neutralise  microbic  and  other  irritants. 
Whether  the  fixed  tissue  cells  of  the  body  have  similar  "  extracellular  " 
action  upon  living  irritants,  or  not,  is  a  matter  that  has  not  yet  been 
ascertained.    There  are  indications  that  this  may  be  so. 

Summary.  —  Thus,  to  sum  up  the  facts  gathered  together  in  this 
chapter,  the  chief  results  of  recent  researches  into  the  functions  of  the 
wandering  cells,  as  they  affect  our  knowledge  of  thd  inflammatory 
process,  would  seem  to  be  the  following :  — 

1.  That  in  the  higher  animals  there  are  several  forms  of  leucocytes. 

2.  That  a  distinction  can  be  made  out  in  the  distribution  of  the 
various  forms,  some  being  characteristic  of  the  blood,  others  of  the  con- 
nective tissue  spaces  and  of  the  coelom  and  coelomic  fluid  in  general. 

3.  That  the  forms  of  cells  accumulating  during  the  inflammatory 
process  consequently  vary  according  to  the  region  of  injury. 

4.  That  a  variation  is  to  be  made  out  also  in  the  rate  of  accumula- 
tion of  the  different  forms  of  cellb:  the  coarsely  granular  oxyphile 
(eosinophilous),  which  in  the  main  are  pre-existent  in  the  connective 
tissue  spaces,  being  attracted  sooner  than  the  finely  granular  oxyphile 
(neutrophile  haemal)  and  the  hyaline  (coelomic)  respectively. 

5.  That  a  further  distinction  is  to  be  made  out  in  the  mode  of  action 
of  these  cells :  the  coarsely  granular  oxyphile  never  act  as  phagocytes, 
but  possess  excretory  properties ;  the  hyaline  and  finely  granular  oxy- 
phile are  characteristically  phagocytic. 

6.  That  the  accumulation  of  leucocytes  is  due  in  part  to  migration, 
in  part  to  proliferation  in  situ. 

7.  That  under  certain  conditions  (what  these  are  and  what  their 
relative  importance  have  yet  to  be  more  fully  worked  out)  the  phago- 
cytes are  capable  of  directly  incorporating  pathogenetic  bacteria.  The 
main  conditions  would  seem  to  be  the  possession  by  the  bacteria  of 
relatively  weak  irritant  or  pathogenetic  properties,  and  by  the  organism 
of  relatively  strong  powers  of  resistance. 

8.  That  under  other  conditions  (where,  for  example,  the  microbes  are 
endowed  with  fuller  irritant  properties,  or  the  constitutional  resistance  is 


94 


SYSTEM  OF  MEDICINE 


lower)  phagocytosis  may  be  preceded  by  an  excretory  process  on  tlie 
part  of  certain  cells,  notably  the  coarsely  granular  oxyphile,  whereby 
apparently  the  vitality  and  irritant  pr'  ^  rties  of  the  microbes  undergo 
a  diminution.  Here  again  we  are  as  yet  ignorant  of  the  exact  value  of 
all  the  factors  leading  to  active  intervention  of  these  excretory  cells. 

9.  That  the  bactericidal  and  antitoxic  action  of  the  blood  serum  and 
body  fluids  outside  the  body  is  due  to  the  liberation  into  these  fluids  of 
bactericidal  and  antitoxic  substances  step  by  step  with  the  disintegration 
of  the  leucocytes. 

10.  That  clearly  this  liberation  of  bactericidal  and  antitoxic  sub- 
stances by  excretion  from  living  cells,  and  by  disintegration,  does  not 
obtain  to  the  same  extent  in  the  fluids  within  the  living  body ;  never- 
theless it  does  occur,  more  especially  as  the  result  of  irritation,  and 
its  occurrence  is  fitted  to  explain  those  cases  in  which  the  amount 
of  phagocytosis  observable  is  not  co-extensive  with  the  disappearance 
of  the  microbic  irritants. 

11.  That  where  the  bacteria  jare  endowed  with  great  virulence,  there 
the  wandering  cells  migrating  to  the  region  are  both  fewer  in  numbers, 
and,  being  killed,  undergo  dissolution  to  a  very  considerable  extent. 
This  dissolution  may  in  itself,  by  the  liberation  of  bactericidal  substances 
into  the  inflammatory  exudation,  hinder  the  proliferation  of  the  microbes 
to  a  greater  or  less  extent.  If,  however,  the  dissolution  be  unaccom- 
panied by  a  massing  of  active  leucocytes  peripherally  around  the  region 
of  irritation,  then  the  microbic  irritants  may  be  carried  away  from  the 
inflammatory  focus,  and  induce  generalised  disease. 

To  complete  this  summary  I  will  here  add  other  conclusions  deduced 
from  a  study  of  the  later  stages  of  inflammation  and  discussed  in  a  later 
chapter  ("  Upon  the  pai't  played  by  the  fixed  Cells  in  the  Inflammatory 
Process  "),  viz. :  — 

12.  In  the  later  stages  of  inflammation  the  growing  fibroblasts  may 
often  be  seen  to  contain  leucocytes  in  process  of  digestion.  Presumably, 
therefore,  a  certain  number  subserve  nutrition. 

13.  Others  are,  in  certain  cases,  recognisable  in  the  lymph-spaces 
outside  the  inflammatory  focus,  containing  the  debris  of  dead  tissue. 
Emigration  can  therefore  occur  as  well  as  immigration. 

14.  The  process  of  development  of  wandering  into  fixed  cells  has 
been  observed ;  but  this  is  the  exception,  not  the  rule. 

15.  The  contrary  process  of  development  of  wandering  cells  from 
degenerating  tissue  (muscle  fibres)  has  also  been  recorded  by  more  than 
one  observer. 


Chapter  2. — The  Inflammatory  Exudation 

Whenever  injury  to  the  tissues  leads  to  vascular  dilation  there  is 
an  increased  effusioii  of  plasma  from  the  blood.  The  extent  of  this 
effusion  varies  greatly;  it  varies  with  the  tissue  affected,  the  state 
of  the  organism,  and  the  quality  and  nature  of  the  irritant.     Dense 


f 


I  'i 


INFLAMMA  TION 


95 


tissue  permits  of  little  exudation,  while  loose  vascular  tissue,  under  the 
action  of  an  irritant  of  no  great  intensity,  may  undergo  great  exudative 
swelling.  There  is,  for  instance,  a  peculiar  liability  in  serous  and 
cutaneous  surfaces  (or  more  truly  in  subserous  and  dermal  layers),  when 
inflamed,  to  manifest  abundant  exudation.  Their  vascularity  and  the 
slight  external  resistance  would  appear  to  explain  this  liability.  There 
is  not  the  same  tendency  to  abundant  exudation  from  mucous  surfaces 
save  where,  as  in  the  alveoli  of  the  lungs,  the  epithelium  is  reduced  to 
a  single  layer  of  delicate  flattened  cells ;  on  the  other  hand  there  is  a 
marked  tendency  towards  serous  infiltration  and  swelling  of  the  sub- 
mucosa.  That  some  general  state  of  the  organism  is  a  factor  concerned 
is  seen  when  virulent  anthrax  bacilli  are  inoculated  subcutaneously  into 
an  ordinary  rabbit  and  into  one  that  has  been  rendered  immune :  in  the 
former  the  exudation  is  of  a  serous  nature,  in  the  latter  little  fluid  is 
exuded  from  the  vessels.  The  effect  of  the  quality  of  the  irritant  is 
observable  upon  comparison  of  the  results  of  inoculation  of  various 
microbes.  Some  cause  little  exudation  of  fluid.  Theso  are  in  general 
of  low  pathogenic  quality,  but  not  always ;  certain  virulent  microbes 
(such  as  those  of  tetanus)  lead,  when  inoculated,  to  relatively  little 
effusion  of  fluid  from  the  vessels.  On  the  other  hand,  it  may  be  stated 
definitely  that  where  in  a  moderately  dense  tissue  the  injection  of  a  pure 
culture  of  a  micro-organism  leads  to  well-marked  exudation,  the  micro- 
organism is  of  high  virulence. 

Can  any  meaning  be  ascribed  to  this  effusion?  Is  it  an  attempt 
at  increased  nutrition  in  the  injured  region?  It  has  been  sug- 
gested, in  accordance  with  Virchow's  theory  of  inflammation,  that 
the  injury,  stimulating  the  surrounding  fixed  cells,  leads  to  increased 
local  metabolism ;  and  that  the  exudation  is  a  means  of  bringing  to  the 
region  the  increased  nourishment  demanded  by  the  increased  cellular 
activity.  But  inasmuch  as  exudation  is  most  marked  in  those  cases 
where  there  is  most  profound  and  rapid  cell  destruction,  and  again  at 
the  early  stage  of  the  inflammatory  reaction,  when  evidences  of  growth 
and  proliferation  of  the  fixed  cells  of  the  region  may  be,  and  most  often 
are,  wholly  wanting,  this  view  can  scarcely  be  upheld.  Yet  at  a  later 
period  of  the  process,  and  again  in  chronic  inflammation,  the  overgrowth 
of  the  connective  tissue  cells  would  appear  to  stand  in  close  relationship 
to  the  over-nutrition  caused  by  the  continued  dilation  of  the  vessels  and 
the  pouring  out  of  excessive  lymph  into  the  tissues.  There  is,  appar- 
ently, a  close  relationship  between  the  increased  exudation  and  inflam- 
matory hyperplasia. 

That  the  exudation  exerts  a  "  flushing  out "  action  is  very  evident  in 
many  cases.  Thus  the  inflammation  induced  by  plunging  an  animal's  leg 
into  hot  water  is  accompanied  by  great  increase  in  the  amount  of  lymph 
obtainable  from  the  efferent  lymphatics  of  the  part.  It  is  shown  also  by 
the  presence  of  streptococci  in  the  lymph  channels  outside  the  area  of 
acute  inflammation  in  erysipelas,  by  the  frequent  implication  of  the 
nearest  lymph  glands  in  suppurative  disturbances,  and  by  the  appearance 


95 


of  lesions,  duo  to  the  direct  action  of  bacterial  products,  in  organs 
far  removed  from  the  focus  of  bacterial  proliferation  in  such  diseases  as 
diphtheria  and  tetanus,  wherein,  as  a  rule,  the  bacteria  remain  strictly 
localised.  It  is  clear  that  the  exudation  into  an  inflamed  area  can  accom- 
plish a  removal  of  irritant  matters.  It  is  clear  also,  from  more  than  one 
of  the  examples  given  above,  that  a  process  which  may  be  beneficial  to 
the  region  of  injury  may  be  harmful  to  the  system  as  a  whole. 

It  is  interesting  to  note  that  this  effect  of  flushing,  in  part  beneficial, 
in  part  harmful,  has,  if  I  may  so  express  it,  gained  a  certain  amount  of 
recognition  on  the  part  of  the  organism.  Where  the  irritant  can  be  con- 
veyed to  the  exterior  an  abundant  exudative  inflammation  generally 
occurs  —  an  abundant  flushing ;  where  it  can  be  conveyed  into  one  of 
the  body  cavities  the  same  holds  good ;  but  here  a  mechanism  is  often 
called  into  action  whereby  the  exudate  with  its  contained  irritants  is  held 
within  the  serous  cavity  for  days  and  weeks  after  all  signs  of  active 
inflammation  have  subsided.  The  organisin,  that  is  to  say,  would  seem 
to  restrain  its  drainage  to  the  general  lymphatic  system.  Where  the 
irritant  is  merely  the  product  of  tissue  change  the  profuse  exudate  is 
rapidly  conveyed  away;  where,  on  the  other  hand,  the  injury  is  of 
bacterial  origin,  the  passage  of  lymph  from  the  focus  of  inflammation, 
is,  generally  speaking,  not  nearly  so  free ;  it  is  of  thicker  consistency 
and  drains  away  si  awly.  In  short,  as  I  have  already  indicated,  where 
the  microbe  is  not  too  virulent  a  cellular  rather  than  a  serous  inflamma- 
tion is  produced ;  and  in  place  of  abundant  flushing  an  increased  anti- 
bacterial and  antitoxic  action  of  the  exuded  lymph  conies  into  play. 

But  besides  this  "  flushing  out "  effect  the  exudation  subserves 
another  purpose,  namely,  dilution  of  the  irritant  and  reduction  of  its 
injurious  properties,  so  that  it  acts  with  lessened  force  upon  the  tissues, 
and  permits  the  wandering  cells  to  be  attracted  to  the  region  where  they 
may  exert  their  functions.  Where  a  comparatively  mild  physical  irritant 
leads  to  abundant  exudation  the  flushing  out  action  appears  to  be  in  the 
ascendant,  where  microbic  irritants  cause  great  local  inflammatory 
oedema,  judging  from  the  less  extensive  lymph  flow  from  the  region,  the 
diluent  action  must  be  regarded  as  the  more  important.  I  have  already 
pointed  out  that  a  relation  may  be  traced  between  the  intensity  of 
bacterial  irritation  and  the  extent  of  the  exudation.  In  short,  there 
may  be  great  exudation  under  two  apparently  opposed  conditions :  in 
the  presence  of  comparatively  mild  physical  irritants,  and  in  that  of 
severe  bacterial  irritants.  In  the  former  case  it  more  especially  sub- 
serves removal,  in  the  latter  dilution  of  the  poison. 

The  fundamental  distinction  between  the  inflammatory  exudation  and 
ordinary  lymph  is  its  richness  in  proteids.  Whether  we  regard  lymph 
as  a  filtrate  pure  and  simple  from  the  blood,  or,  with  the  majority  of 
modern  physiologists,  follow  Heidenhain  in  regarding  it  as  the  result  of 
a  selective  filtration,  it  is  eminently  probable  that  in  inflammation  the 
exudate  approaches  in  its  composition  more  nearly  to  the  blood  plasma 
than  does  ordinary  lymph.     The  dilatation  of  the  cauillaries,  the  couse- 


I)  ii 


INFLAMMA  TION 


97 


ill 


quent  thinning  of  the  endothelial  layer  with,  it  may  be,  the  opening 
of  some  lacunae  between  the  individual  cells,  and  the  direct  action  of 
the  irritant  upon  these  cells,  may  all  be  expected  to  aid  the  transuda- 
tion. In  this  way  the  amount  of  proteid  matter  in  the  lymph  may  be 
increased.  But  equally  important  must  be  the  addition  of  proteids  due 
to  the  breaking  down  of  leucocytes  and  tissue  cells.  I  have  already 
discussed  this  destruction  of  the  cells,  and  need  not  here  give  the  evi- 
dence of  its  occurrence. 

In  addition  to  the  proteids  the  inflammatory  lymph  may  contain 
other  substances  worthy  of  more  than  passing  note.  Of  these  the  more 
important  are  ferments,  the  results  of  proteolysis  (notably  fibrin  and 
its  precursors,  and  peptones),  and  in  many  cases  mucin,  together  with 
bactericidal  substances,  and,  where  bacteria  are  present,  the  products 
of  their  growth. 

The  presence  and  amount  of  these  substances  depend  largely  upon 
the  intensity  and  character  of  the  inflammation.  Thus  the  total  quantity 
of  proteids,  and  the  proportion  of  fibrin,  albumin,  and  globulin  present, 
vary  within  wide  limits.  The  following  table '  of  observations  made  by 
Dr.  Halliburton  shows  well  this  variation  in  proteids,  and  the  difference 
existing  between  inflammatory  exudations  and  dropsical  effusions :  — 


rl 

I' 


Pleural  Fluid  from 

8p.  Or. 

Percontago  Quantity  of 

Total 
Proteid. 

Fibrin. 

Serum- 
globulin. 

Serum- 
albumin. 

Acute  pleurisy,  Case  1 
„            „        Case  2 
Case  3 
Hydrothorax        .        .  \ 
Average  of  three  cases  j 

1023 
1020 
1020 

1014 

5123 

3-4371 

5-2018 

1-7748 

0-016 

0-0171 

0-1088 

0-0086 

3-002 

1-2406 

1-76 

0-6137 

2-114 

1-1895 

3-330 

1-1557 

Between  the  amount  of  fibrin  present  in  exudations  and  the  amount 
of  peptones  there  is  an  inverse  ratio.  Peptones  are  especially  devel- 
oped in  connection  with  suppurative  inflammation;  and  the  more  an 
inflammation  tends  to  be  suppurative  the  greater  is  the  breaking  down 
of  the  fibrin,  as  also  of  fixed  and  wandering  cells,  and  the  more  evident 
the  production  of  peptones,  until  in  chronic  abscess-formation  of  fair 
extent  the  peptones  pass  into  the  general  circulation,  and  are  excreted 
and  recognisable  in  the  urine. 

Into  the  discussion  of  the  mode  of  formation  of  fibrin  I  need  not  en- 
ter here,  intimately  connected  as  the  subject  is  with  the  inflammatory 
process.  The  greater  text-books  of  Physiology  enter  exhaustively  into 
the  matter.     Suflice  it  to  say  that,  as  in  the  blood,  a  direct  relationship 

1  Theso  fij^ures  aro  thoroughly  ia  accord  with  those  of  other  analyses  by  Beuss, 
Hofiuaun,  Muhu,  and  Letulle. 


VOL.  I 


B 


97 


98 


SYSTEM  OF  MEDICINE 


B0US8, 


is  made  out  between  the  breaking  down  of  leucocytes  and  the  develop- 
ment of  this  substance  in  inflammatory  exudations. 

It  is  in  connection  with  inflammation  affecting  serous  and  epithelial 
surfaces  ^  that  fibrin  is  most  clearly  recognisable,  forming,  it  may  be, 
thick  coatings  of  the  badly-named  "  inflammatory  lymph  "  over  the  in- 
flamed surfaces.  This  deposit  is  in  all  respects  comparable  to  the  forma- 
tion of  thrombi  in  the  blood-vessels.  Here,  as  there,  the  deposit  occurs 
only  when  the  endothelium  has  undergone  destruction  and  the  roughened 
sub-endothelial  tissues  are  exposed.  And  here  also  the  fibrin  may  be 
deposited  either  in  filamentous  or  homogeneous  and  hyaline  form  accord- 
ing to  circumstances. 

Leaving  out  of  account  coagulation-necrosis  as  not  occurring  in 
direct  connection  with  exudates,  it  may  be  said  that  similar  fibrin  for- 
mation is  frequently  recognisable  in  connection  with  primary  inflamma- 
tion of  parenchymatous  tissues." 

The  beneficial  effects  of  fibrin  formation  in  serous  cavities  have  been 
rendered  abundantly  manifest  by  the  increase  in  abdominal  surgery.  No 
one  who  has  followed  any  considerable  number  of  operations  for  appendici- 
tis can  have  failed  to  remark  how,  in  case  after  case,  despite  the  intricacy 
of  the  abdominal  coils  and  their  mobility,  the  strongly  irritant  matter  pro- 
duced by  gangrene  of  the  appendix,  or  oozing  through  perforations  in  it, 
is  restricted  within  a  relatively  small  space  by  the  surrounding  fibrinous 
adhesions  which  form  rapidly  between  the  intestinal  loops.  ]?y  this  mean^ 
alone  the  peritonitis  is  restricted  and  "  regional,"  instead  of  being  general- 
ised from  the  onset.  Even  when  inflammation  (as  in  pericarditis)  affects 
tlie  whole  extent  of  a  serous  cavity,  the  layer  of  fibrin  acts  as  a  protective 
coat  closing  the  lymphatic  stomata,  hindering  the  free  absorption  of  the 
morbid  material  by  the  lymph  and  blood-vessels,  and  filtering  bacteria 
out  of  such  fluid  as  does  find  its  way  through  to  the  tissues  beneath.  It 
is  not  a  little  remarkable  to  call  to  mind  how  case  after  case  of  purulent 
pericarditis  or  purulent  pleurisy  may  be  examined  in  which,  despite  the 
intense  suppurative  disturbance  in  the  serous  cavity,  the  tissues  at  the 
other  side  of  the  deposit  of  fibrin  —  the  myocardium  or  the  lung  tissue 
—  show  little  or  no  tendency  to  abscess  formation.  Let  there  be  primary 
abscess  formation  or  gangrene  in  the  lung,  and  perforation  of  the  pleura 
and  hydrothorax  may  supervene;  pleurisy,  however  intense,  does  not 
lead  to  this  unless  complicated  by  other  disease.  Let  there  be  primary 
or  metastatic  abscess  in  the  myocardium,  then  there  maybe  aneurysm  and 
rupture  of  the  heart;  yet  such  rupture  produced  by  extension  inwards  of  a 
purulent  pericarditis  is  of  the  utmost  rarity.  Let  there  be  inflammation 
originating  in  the  submucosa  of  the  intestines,  as  in  enteric  fever,  and 

1  Of  epithelial  surfaces,  more  especially  those  covered  by  a  single  cell  layer,  as  notably 
the  pulmonary  alveoli. 

2  Where  there  are  abundant  and  distensible  lymph  channels  there  extensive  clotting 
may  be  seen  in  the  lymph.  This  is  peculiarly  well  marked  in  the  contagious  pneumonia 
of  cattle  (contagious  pleuro-pneumonia).  In  acute  intlammation  of  various  organs,  by 
appropriate  methods  of  staining,  similar  formations  of  threads  uf  fibrin,  often  starting 
from  colls  as  centres,  may  be  observ  d  in  the  tissue  spaces. 


I  S« 


/" 


INFLAMMA  TION 


99 


perforation  may  result ;  general  peritonitis,  while  often  due  to  perfora- 
tion, never  —  so  far  as  I  can  call  to  mind  —  directly  induces  that  event. 
In  all  these  cases  the  natural  protective  layer  of  the  serous  surface  is 
removed  or  gravely  injured  at  a  very  early  stage ;  and  the  layer  of  fibrin, 
replacing  the  serous  endothelium,  forms  an  effective  barrier.  I  may  add 
that  the  mucin,  extruded  so  as  to  form  a  layer  over  inflamed  mucous 
surfaces,  presents  a  similar  protective  action. 

Passing  now  to  the  ferments  and  ferment-like  bodies  present  in 
the  exudate,  I  may  briefly  state  that  these  are  not  only  generated  and 
excreted  by  the  pathogenetic  bacteria  present,  but  are  liberated  by  the 
breaking  down  of  the  wandering  cells.  Abundant  evidence  of  the  exist- 
ence of  bacterial  ferments  capable  of  acting  upon  proteids,  gelatine, 
sugars,  etc.,  is  supplied  by  the  study  of  the  growth  of  these  microbes 
outside  the  body.  That  ferments  also  originate  from  the  wandering 
cells  has  been  demonstrated  by  Leber,  who,  placing  pieces  of  copper  in 
the  anterior  chamber  of  the  eye,  thereby  produced  a  purulent  collection 
devoid  of  microbes,  and  showed  that  the  exudate  was  capabl  >.  of  digest- 
ing proteid  matter. 

It  would  seem,  therefore,  that,  more  especially  in  pyogenetic  inflam- 
mation, the  removal  of  dead  tissue  cells  and  dead  leucocytes  may,  to  a 
large  extent,  be  due  to  the  action  of  the  inflammatory  exudations,  apart 
from  any  phagocytic  action  on  the  part  of  living  active  cells ;  although 
this  also  comes  often  into  play. 

Of  the  bactericidal  substances  present  in  the  inflammatory  exudate 
I  have  already  treated.  Here  I  need  only  repeat  that  the  researches  of 
Kanthack  and  Hardy,  of  Denys,  and  lastly  of  Pfeiffer  and  Metschnikoff, 
fully  prove  that  substances  capable  either  of  destroying  microbes  or  of 
hindering  their  growth  are  present  therein. 

Summary.  —  To  sum  up  what  is  known  concerning  the  inflammatory 
exudate,  it  may  be  said  — 

1.  That  the  exudate  varies  in  amount  and  in  character  with  (a)  the 
nature  and  intensity  of  the  irritant,  (6)  the  condition  of  the  organism, 
(c)  the  region  of  irritation. 

2.  That  while  it  undoubtedly  augments  the  nutrition  of  the  affected 
region,  increased  nutrition  at  the  early  stage  of  an  acute  inflammatory 
process  would  not  seem  to  be  of  benefit  or  to  play  any  important  part. 
At  a  later  stage  and  in  chronic  inflammation  the  increased  nutrition  in 
all  probability  aids  the  hyperplasia. 

3.  That  in  many  cases  the  exudate  exerts  a  beneficial  action  by 
flushing  out  the  injured  area. 

4.  That  the  exudate  plays  an  important  part  in  diluting  the  irri- 
tant. 

6.  That  the  development  of  fibrin  in  certain  inflammatory  exudates 
is  associated  with  the  breaking  down  of  the  wandering  cells,  and  is  of 
manifest  benefit  in  so  far  as  it  cinnimscribes  the  inflamed  area,  and 
prevents  the  ])aBsago  of  morbid  material  outwards. 

0.  That  the  uxudute  may  possess  digestive  functions,  causing  the  pro- 


99 


loo 


SYSTEM  OF  MEDICINE 


duction  of  peptones ;  the  ferments  being  developed  from  the  cells  alone 
when  the  exudate  is  aseptic,  from  these  and  the  microbes  together  where 
pathogenetic  microbes  are  present. 

7.  That  the  exudate  may  further  contain  substances;  generated  by 
the  cells,  capable  of  hindering  bacterial  growth,  and  of  destroying 
pathogenetic  microbes. 


Chapter  3.  —  The  Part  played  by  Blood- Vessels 

The  study  of  the  action  and  function  of  the  leucocytes  in  inflamma- 
tion has  profoundly  modified  our  conception  of  the  inflammatory  process. 
When  the  leucocytes  were  regarded  as  purely  passive  agents,  and  their 
diapedesis  as  purely  secondary  to  moditied  conditions  of  the  blood  cur- 
rent and  of  the  vascular  walls,  the  theory  of  Cohnheim  was  that  most 
generally  accepted.  And  this  theory  regarded  the  changes  in  the  vessels 
as  of  the  first  importance.  Thus  it  was  that  for  several  years  our  atten- 
tion was  mainly  concentrated  upon  the  determination  of  the  various 
chaages  of  the  vessel  walls,  and  of  the  mechanism  whereby  these  chiinges 
were  brought  about.  Nowadays  less  attention  is  directed  to  this  side  of 
the  inflammatory  process,  and  it  may  be  said  that  during  the  last  ten 
years  little  advance  has  been  made  in  determining  the  mechanism  of  the 
dilatation  that  accompanies  inflammation. 

The  subject,  indeed,  is  beset  with  difliculties.  It  is  most  difficult 
to  observe  the  changes  that  occur  in  the  cells  forming  the  endothelium 
of  the  congested  vessels ;  we  are  still,  for  instance,  far  from  being  sure 
whether  the  opinion  of  Arnold  is  correct,  namely,  that  the  leucocytes, 
and,  it  may  be,  a  large  portion  of  the  exuded  plasma,  find  their  way  out 
through  the  dilated  stomata  between  the  endothelial  cells ;  or  whether 
the  leucocytes  pass  directly  through  these  cells  as  one  soap  bubble  may 
be  passed  through  another.  And  when  we  come  to  discuss  whether  the 
inflammatory  exudation  be  a  filtration,  or  whether,  on  the  other  hand,  it 
be  more  of  the  nature  of  an  excretion,  or  what  may  be  termed  a  selective 
filtration  —  certain  components  of  the  blood  plasma  being  permitted  to 
pass  through,  while  others  are  withheld  —  we  are  met  with  the  ditticulty 
that,  of  the  extravasated  leucocytes,  a  varying  pro})ortion  undergo  rapid 
destruction  and  dissolution.  Thus,  in  analysing  the  inflammatory 
serum,  we  are  not  dealing  simply  with  the  extravasated  fluid,  but  with 
a  fluid  which  in  addition  contains  ])n)teid  and  other  constituents  derived 
largely  from  broken-down  white  (•or])U8cles,  and  in  part,  it  may  be,  from 
the  modified  cells  of  the  inflamed  area. 

Though  Arnold's  observations  upon  the  altered  condition  of  the 
vascular  endothelium  in  inflannnation  ap))ear  at  first  very  convincing, 
upon  further  study  tliey  seem  at  most  to  indii-ato  tluit  with  dilation 
of  the  vessels  ther(>  is  an  increase  in  the  size  of  tiie  sjKices  between  the 
endothelial  cells.  They  do  not,  however,  prove  that  these  are  other  than 
virtual  spaces  filled  with  intercellular  substance;  and  indeed  Arnold 
himself  came  eventually  to  the  conclusion  that  some  sucli  substance  was 


IN  FLAM  MA  TION 


lOI 


present  filling  them.  The  fact  that  viscid,  gelatinous  substances  injected 
into  the  circulation  may  be  detected  passing  through  these  stigmata  is 
not  a  proof  that  the  spaces  are  actual ;  all  it  proves  is  that  the  walls 
are  weaker  in  these  regions:  it  must  be  remembered  that  increased 
force  and  increased  intravascular  pressure  are  necessary  to  promote  the 
passage  of  the  injected  mass  along  the  vessels.  The  passage  of  the  mass 
through  the  walls  may  therefore  be  an  "  artefact." 

There  is  this  further  difficulty  in  the  assumption  that  these  are  actual 
spaces — that  in  acute  inflammation  the  exuded  fluid  in  general  contains 
a  smaller  quantity  of  proteids  than  does  the  blood  plasma.  It  is  true, 
no  doubt,  that  the  stigmata  are  so  small  they  may  possibly  act  like  the 
pores  of  a  filter,  and  consequently  may  not  permit  the  free  passage  of 
certain  constituents  of  blood  plasma.  Yet,  granting  all  this,  if  the  same 
principles  be  in  action  as  those  governing  the  ordinary  (non-inflamma- 
tory) transudation,  we  must,  with  Heidenhain,  be  inclined  to  regard  the 
endothelium  as  playing  not  a  i)assive,  but  an  active  role.  To  enter  into 
the  large  subject  of  the  nature  of  lymph  would  be  to  pass  too  far  afield ; 
recent  researches,  on  the  whole,  favour  the  view  that  the  inflammatory 
exudation  is  not  a  mere  filtrate,  but  is  the  result  of  a  selective  activity 
on  the  part  of  the  endothelial  cells. 

We  have  not  a  little  evidence  that  these  cells  play  an  important  part 
in  the  vascular  phenomena  of  inflammation.  To  their  power  of  taking  up 
microbes  and  acting  as  phagocytes  I  have  already  referred ;  into  their 
connection  with  the  slowing  of  the  blood  stream  I  shall  enter  later. 
Here  I  would  point  out  that  microscopically  these  cells  can  be  seen  to 
alter  during  the  inflammatory  process;  they  become  enlarged  and 
project  into  the  lumen  of  the  smaller  vessels,  and  in  my  experience  this 
enlargement  affects  not  only  the  cell  bodies,  but  also  the  nuclei,  which 
at  the  same  time  would  seem  to  contain  more  chromatin  and  to  stain 
more  intensely.  In  cases  of  chronic  inflammation  the  enlargement  is 
followed  by  proliferation,  notably  in  the  arterioles  and  capillaries,  —  a 
process  which  may  lead  to  the  ultimate  occlusion  of  these  small  vessels. 
And  in  acute  inflammation,  according  to  numerous  observers,  mitosis  is 
to  be  seen  occurring  in  these  endothelial  cells  at  an  earlier  period  than 
in  the  surrounding  tissues. 

A  further  and  very  important  process  intimately  connected  with  the 
proliferation  of  the  endothelium  of  the  cajjillaries  is  the  formation  of 
new  v(!S8els  as  tlio  result  of  continued  inflammation.  It  is  true  that 
llindflciscih  and  others  have  described  this  as  being  brought  alnjut  by 
vaso-formative  cells  situated  externally  to  the  vessels ;  and  that  others 
have  advanced  so  far  as  to  suggest  that  there  are  cells  in  the  newly- 
forming  granulation  tissue  which  become  hollowed  out  and  gain  attach- 
ment to  the  pre-existing  capillaries  in  a  manner  wholly  similar  to  that 
observable  in  the  vascular  zoni!  of  the  chicken  embryo.  I  hav(i  sought 
for  such  intracellular  deV(!lo|>nient,  but  never  have  I  seen  the  slightest 
indication  thereof;  nor  again  have  1  been  able  to  discover  cells 
arranging  themselves  after  the  method  described  by  Kindfleisch  iu 


I03 


SYSTEM  OF  MEDICINE 


\ 


columns  or  parallel  rows  preparatory  to  the  passage  of  blood  between 
them  ancJ  to  the  formation  of  a  capillary. 

The  ser.rch  for  the  earliest  signs  of  new  capillaries  is  a  matter  of 
peculiar  difficulty.  I  will  not  peremptorily  state  that  Eindileisch  mis- 
took an  arrangement  of  cells  not  unf  requently  seen  in  granulation  tissue 
for  stages  in  the  development  of  new  vessels.  I  will  only  say  that  my 
own  observations  coincide  with  those  of  Arnold,  and  of  the  majority  of 
those  who  have  more  recently  studied  the  question,  and  lead  me  to  regard 
the  formation  of  new  capillaries  as  originating  from  the  endothelium  of 
the  vascular  loops  already  in  existence. 

The  first  step  in  the  process  is  often  recognisable,  in  cases  of  pleurisy 
and  pericarditis,  in  the  projection  of  loops  of  pre-existing  capillaries 
beyond  the  line  which  indicates  where  the  serous  endothelium  used  to 
be,  and  into  the  fibrinous  clot  now  adherent  to  the  sub-endothelial  layer. 
Such  loops  are  markedly  distended,  and  "  point,"  as  it  were,  at  riglit 
angles  to  the  denuded  surface.  A  similar  pointing  or  giving  way  of  the 
wall  along  the  convex  margin  of  the  loop  is  also  to  be  made  out  not 
unfrequently  ir  newly-developed  capillaries.  In  these  there  is  not,  as 
might  be  exnt  '  \  a  thinning  of  the  endothelium  along  this  outer  mar- 
gin, but  certa  le  cells  on  the  contrary  appear  large  and  active.  At 
times  a  small  ..  ^...^  protrnt"ion  of  the  vessel  wall  can  be  detected  in  the 
region  of  pointing.  This  isj  best  seen  in  the  capillaries  that  are  them- 
selves but  newly  formed,  and  composed  of  nothing  but  a  layer  of  endo- 
thelial cells.  In  this  layer  the  protrusion  can  bo  made  out  to  be  in 
direct  continuity  with  the  endothelial  cells  of  the  region.  At  first  it 
is  solid,  but  in  the  later  stages  it  can  be  seen  to  be  nucleated,  and  to  be 
growing  by  proliferation  of  the  endothelial  cells  which  thus  jut  out- 
wards. Even  before  any  further  change  is  noticeable  in  this  projecition 
from  the  capillary  wall  it  may  be  seen  to  be  united  with  a  similar  pro- 
cess originating  from  a  neighbouring  vascular  loop.  Finally,  it  would 
appear  that  the  joined  processes  become  hollowed  out,  and  thus  are 
developed  into  fully-formed  capillary  loops.  It  seems  impossible  to 
make  precise  observations  on  tlie  phenomena  of  now  vascular  formation 
in  its  successive  stages.  I  can  b>it  state  that  these  appear  to  be  the 
steps  of  the  process.  By  what  means  the  new  vascular  projections  join 
together  to  form  loops  we  are  ignorant.  Metschnikoff  suggests  that 
there  must  be  an  attraction  between  tlie  neighbouring  projections  —  a 
chemiotaxis  —  leading  them  to  come  into  apposition;  this,  however,  is 
no  more  than  a  suggestion.  That  they  do  join  is  very  clear  to  those  who 
have  stmlied  granulation  tissue,  or  have  observed  the  vascular  network 
connecting  the  previously  separated  surfaces  of  a  wound. 

A  further  function  of  the  vt^ssol  walla  is  to  be  seen  in  the  slowing  of 
the  blood  current.  It  is  difficult,  and  in  fact  impossible,  to  explain  this 
slovring  l)y  altered  diameter  of  the  arteries  and  veins.  The  alterations 
observed  in  the  diameters  of  the  vessels  of  the  inflamed  area  are  sucli  as, 
acting  alone,  would  led  to  incnMised  rate  of  flow.  Nor  again  is  the 
a}>parent  amount  of  exudation,  and  of  lymph  flow  from  the  att'ected 


11 


2J\rFLA  MM  A  TION 


103 


11 


part,  sufficient  to  make  it  probable  that  (as  Wharton  Jones  first  suggested) 
the  sloAving  is  in  the  main  due  to  the  concentration  of  the  blood,  relative 
drying  of  the  corpuscles,  and  consequent  increase  of  friction :  while  this 
may  be  an  adjuvant  we  must,  I  think,  tind  some  more  potent  factor. 
What  this  factor  is  was  pointed  out  long  ago  by  Lister,  who,  in  1858, 
noticed  that  coincident  wrih  the  slowing  of  the  blood  stream,  the  cor- 
puscles move  sluggishly  along  the  vessel  wall  as  though  attracted  by  it. 
Lister  essayed  to  pro\e  this  by  ai:  experiment  performed  previously  by 
Weber.  He  ligaturod  a  frog's  leg,  then  irritated  a  portion  of  the  web  by 
a  little  mustard,  r.ud  fourid  that,  although  the  blood  current  had  ceased, 
there  was  never'^heless  an  accumulation  of  corpuscles  in  the  vessels  of  the 
irritated  area,  the  corpuscles  gliding  into  the  affected  region  and  becom- 
ing adherer.c  there.  Other  observers  have  shown  that  this  accumulation 
is  not  due  to  increased  adhesiveness  of  the  red  corpuscles,  inasmuch  as 
similar  skwin<T  .,i-d  stasis  may  be  induced  if  the  blood  of  the  frog's  leg 
be  replacfd  by  milk  fjid  the  web  irritated.  In  this  case  there  is  a 
gradual  slowing  of  tht  stream  of  milk  and  accumulation  of  the  fatty 
globules  in  the  inflamed  area.  While  in  Lister's  experiment  the  transu- 
dation of  the  plasma  might  explain  the  accumulation  of  the  corpuscles, 
in  this  latter  instance,  as  in  ordinary  inflammation,  the  observed  transuda- 
tion is  insufficient  to  account  for  the  accumulation  and  slowing.  Although 
I  cannot  accept  las  experiment  as  conclusive,  I  am  forced  to  concur  with 
Lister  to  ohis  extent,  that  in  inflammation  the  cndotheliiyn  of  the  vessel 
walls  becomes  altered,  the  cells  becoming  enlarged.  With  this,  as  evi- 
denced by  the  conduct  of  the  white  corpuscles,  they  become  more 
adhesive,  and  this  adhesiveness  with  the  associated  increased  friction 
between  the  vascular  walls  and  contents  I  regard  as  the  first  factor  in 
biinging  aV.  ut  the  slowing  of  the  blood  stream.  Let  the  current  once 
accelerated  be  rendered  slower  by  this  increased  friction,  then  transu- 
dation may  accentuate  the  accumulation  of  corpuscles. 

Summary.  —  While  there  is  very  much  yet  to  be  learned  concerning 
the  part  played  by  the  blood-vessels  in  inflammation,  and  while  our 
present  knowledge  of  this  branch  of  the  subject  can  only  be  regarded 
as  very  imperfect,  the  following  may,  I  think,  safely  be  said  to  epitomise 
what  is  known  at  the  present  uime :  — 

(1)  That  the  vascular  walls,  and  more  especially  the  endothelial  cells 
linipg  the  capillaries,  play  an  active  and  not  a  passive  part  in  the  in- 
flamed area. 

(2)  These  cells  have  the  power  of  throwing  out  pseudopodia  and 
of  taking  up  non-motile  bacteria. 

(3)  They  are  larger  and  more  prominent  during  inflammation  than 
they  are  under  conditions  of  health. 

(4)  From  them  are  developed  the  new  vascular  loops  in  cases  of 
more  chronic  inflammation. 

(5)  They  would  seem  to  become  more  adhosive  in  inflammation,  and 
by  this,  in  the  hrst  place,  to  lead  to  the  adhesion  of  the  louco(!yte8  and 
red  corpuscles  to  their  walls. 


I04 


SYSTEM  OF  MEDICINE 


(6)  Similarly  they  would  seem  to  cause  an  increased  resistance  to  the 
passage  of  the  blood  current,  and  in  this  way  tend  to  slow  the  rate  of 
blood  flow. 

(7)  The  slowing  of  the  stream  may  further  be  aided  by  the  passage 
through  the  walls  of  increased  amounts  of  fluid  from  the  blood. 

(8)  It  is  impossible  by  analysis  of  the  inflammatory  exudation  to 
determine  whether  this  be  a  mere  filtrate  or  be  the  result  of  a  selective 
activity  of  the  endothelium.  On  the  whole,  taking  into  account  the 
observations  made  upon  ordinary  lymph,  the  latter  would  appear  the 
moid  probable. 

Other  properties  of  the  blood-vessels  in  respect  of  inflammation  will 
be  better  discussed  in  a  later  section  in  connection  with  the  discussion 
of  the  part  played  by  the  nerves. 


Chapter  4. — On  the  Passage  op  Corpuscles  out  op  the  Vessels 

By  his  researches,  Cohnheim  (1867)  forcibly  attracted  the  attention  of 
pathologists  to  the  diapedesis  of  leucocytes  in  inflammation — aproo^ss 
which  had  already  been  described  years  before  by  Addison  (1843)  and 
Waller  (1846)  in  England ;  and  yet  earlier  (though  without  grasp  of  the 
connection  between  the  diapedesis  and  inflammation)  by  Dutrochet,  in 
France  (1828).  Cohnheim  recognised  the  amoeboid  nature  of  the  leuco- 
cytes, and  saw  that  once  outside  the  vessels  they  moved  actively,  but 
eventually  he  could  not  discover  that  their  penetration  of  the  vessel  walls 
was  anything  but  passive ;  and  this  failure  on  his  part  to  recognise  the 
true  nature  of  diapedesis  confirmed  him  yet  more  strongly  in  the  view 
that  the  all-important  factors  in  the  inflammatory  state  were  the  changes 
in  the  vessel  walls,  and,  it  may  truly  be  said,  arrested  his  advance 
towu-ds  a  fuller  comprehension  of  the  subject. 

It  must  be  acknowledged  that  there  is  much  which  would  seem  to 
support  this  view  of  the  passivity  of  the  leucocytes.  No  one  is  pre- 
l)ared  to  attribute  active  movements  to  the  red  corpuscles,  nevertheless 
in  inflammation  a  certain  number  of  these  escape  through  the  vessel 
walls.  In  the  inflammation  affecting  some  organs,  notably  the  lungs, 
the  number  effecting  a  passage  is  very  considerable.  If,  then,  the  red 
corpuscles  emerge  passively,  why  should  not  the  emergence  of  the  white 
bo  passive  also  ?  Add  to  this  the  very  important  observations  made  by 
Cohnheim,  that  where  the  circulation  is  arrested  by  compression  of  the 
artery  there  diapedesis  ceases.  This,  if  invariably  true,  would  seem  to 
indicate  that  when  once  by  changes  in  the  vessel  the  leucocytes  adhere 
to  the  wall,  the  further  passage  through  that  wall  is  due  to  the  ms  a 
tevgn  of  the  blood  pressure. 

Tliiii,  however,  is  not  a  safe  deduction  to  draw  from  the  experiment  re- 
ferred lio.  When  the  artery  of  an  inflamed  area  is  comjjressed  the  stojipajro 
of  the  blood  stream  not  only  reduces  the  pressure,  but  also  affocts  the 
(piality  of  the  blood  and  the  conditions  of  the  vessel  walls ;  moreover,  it 
must  |)rofoundly  affect  the  vitality  and  activity  of  the  contained  leucocytes. 


IN  FLAM  MA  TION 


roS 


i,  ;■» 


! 


These  considerations  alone  render  the  experiment  valueless  as  a  proof  of 
the  passive  nature  of  the  diapedesis.  Again  the  passage  outwards  of  red 
corpuscles  does  not  occur  in  the  earliest  stages  of  reaction  to  irritation ; 
it  never  precedes  the  diapedesis  of  the  leucocytes  (save  where  there  is 
gross  injury),  but  follows  it.  A  capillary  or  small  vein  in  the  inflamed 
frog's  web,  for  example,  may  be  seen  wholly  filled  with  corpuscles,  the 
peripheral  zone  being  quite  annihilated,  and  numerous  red  corpuscles 
lying  in  immediate  contact  with  the  wails ;  nevertheless  at  first  leucocytes 
only  are  seen  to  emigrate.  This  difference  must  be  due  to  some  special 
property  of  these  cells.  The  leucocytes  in  the  blood  stream  are  not 
necessarily  globular  passive  agents,  but  they  are  capable  of  independent 
movement.  Leber,  in  his  long  series  of  studies,  has  pointed  out  that  if, 
with  due  precautions,  a  hooked  glass  tube  (closed  at  its  outer  end  where 
it  catches  into  the  incision  in  the  wall)  be  inserted  into  a  large  vein 
no  thrombosis  may  be  set  up  around  the  intravascular  portion,  and  yet, 
upon  removal,  a  large  collection  of  leucocytes  may  be  found  in  the  tube, 
attracted  by  a  drop  of  mercury  placed  within  it,  with  normal  salt  solu- 
tion. (Mercury  is  a  substance  which  within  the  tissues  leads  to  an 
accumulation  of  leucocytes.)  Here,  then,  there  must  be  active  attrac- 
tion and  active  movement  of  the  leucocytes  within  the  blood  stream. 
And  Lavdowsky  has  described  very  exactly  what  other  observers  had 
also  noted,  namely,  that  in  inflammation  the  leucocytes  in  the  outer  zone 
of  the  blood  stream  do  not  simply  adhere  passively  to  the  wall,  but  move 
backwards  and  forwards  before  they  attach  themselves  and  emigrate,  as 
though  seeking  for  a  point  of  less  resistance.  At  times  this  movement 
is  in  a  direction  opposite  to  that  of  the  blood  current. 

If,  then,  both  within  and  without  the  vessels,  the  leucocytes  can  be 
actively  amoeboid,  it  is  strange  that  they  should  be  passive  in  the  pro- 
cess of  diapedesis  which  to  the  eye  has  so  characteristically  amoeboid 
an  appearance. 

As  above  stated,  the  compression  of  the  artery  passing  to  an  in- 
flamed area  is  in  most  cases  sufficient  to  arrest  diapedesis  in  that  area, 
and  I  have  suggested  that  this  arrest  may  be  due  to  the  altered  envi- 
ronment of  the  leucocytes.  Now,  if  an  embryonic  form  be  taken,  in 
which  the  tissues  would  seem  to  possess  greater  inherent  vitality  coupled 
with  less  sensibility,  the  arrest  does  not  necessarily  occur.  Tims, 
Metschnikoff  has  noted  that  diapedesis  of  the  leucocytes  can  be  fol- 
lowed in  the  tadpole's  tail  after  the  animal  has  been  curarised  to  such 
an  extent  that  the  heart  has  ceased  to  beat  and  the  blood  in  the  capil- 
laries has  been  brought  to  a  standstill. 

It  is  evident,  therefore,  that  with  our  present  knowledge  wo  must 
regard  the  diapedesis  of  the  leucocytes  as  an  active  migration,  and  mtist 
look  upon  the  blood  pressure,  the  disposition  of  the  blood  stream,  and 
the  altered  condition  of  the  endothelium  of  the  dilated  vessels  as  adju- 
vants in  the  process.  The  slowing  of  the  blood  stream  and  the  diminished 
pressure  in  the  inflamed  capillaries  render  it  more  easy  for  the  Icticocy tea 
to  accumulate  close  to  the  vessel  wall ;  the  dilation  of  the  vessels  and 


io6 


SYSTEM  OF  MEDICINE 


of 
ed 


consequent  thinning  of  the  walls,  with  the  opening,  perhaps,  of  larger 
spaces  of  cemout  substances  or  stigmata  between  the  individual  endo- 
thelial cells,  render  it  more  easy  for  the  leucocytes  to  accomplish  the  pas- 
sage ;  but  the  movement  from  within  the  capillaries  to  the  tissue-spaces 
outside  is  an  active  process  due  to  amoeboid  movement  of  the  leucocytes 
themselves.  The  continuity  of  the  vessel  wall  once  destroyed,  other 
cells  —  red  corpuscles  —  may  be  pressed  passively  through  the  walls. 

If  this  view  be  accepted,  we  are  bound  to  look  beyond  Cohnheim's 
limit  of  changes  in  the  vessel  wall  for  the  stimulus  which,  originating  in 
the  area  of  irritation,  acts  upon  the  vessel  wall  and  the  leucocytes  in 
contact  with  it ;  and,  having  first  set  up  chan-res  in  the  former,  so  reacts 
upon  the  latter  that  they  emigrate ;  or,  to  put  it  in  other  words,  are  at- 
tracted out  of  the  capillaries  towards  the  focus  of  irritation.  It  has 
already  been  shown  that  the  movement  of  wandering  cells  in  the  tissue  is 
due  to  the  attraction  of  a  diffusible  product  of  bacterial  growth  and  of 
tissue  change,  and  of  sundry  organic  and  inorganic  materials — a  force  to 
which  the  name  of  positive  chemiotaxis  has  been  given.  This  chemiotaxis 
must  be  invoked  to  explain  the  active  emigration  of  the  leucocytes  from 
the  capillaries,  and  again  to  explain  its  cessation  under  other  conditions. 
Thus,  while  the  exposed  mesentery  of  a  frog  is  a  tissue  in  which  diape- 
desis  can  be  observed  with  facility  under  ordinary  conditions,  if  it  be 
washed  with  a  weak  solution  of  quinine  the  leucocytes  in  the  vessels 
remain  f  lobular,  cease  to  adhere  to  the  walls,  and  do  not  emigrate.  This 
fact,  fi)  >t  noted  by  Binz,  has  been  confirmed  by  several  observers,  among 
whom  Disselhorst  made  out  also  that,  if  these  same  leucocytes  be  re- 
moved from  the  vessels,  they  exhibit  their  usual  amoeboid  movements. 
The  quinine  has  not  paralysed  them,  as  Binz  supposed ;  but,  as  Metsch- 
nikoff  pointed  out,  it  has  neutralised  the  previous  positive  attraction,  a 
negative  or  repulsive  chemiotaxis  being  brought  into  play.  It  is  diffi- 
cult to  see  how  the  above  facts  can  be  otherwise  explained. 

The  view  that  diapedesis  is  an  active  process  gains  further  support 
from,  and  at  the  same  time  explains  certain  interesting  observations 
made  by,  Bouchard,  Roger,  and  Ruffer.  These  observers  have  independ- 
ently shown  that  in  sundry  instances  the  results  of  local  injection  of  viru- 
lent cultures  are  greatly  modified  if,  shortly  before  or  coincidently,  the 
microbes  and  their  products  are  introduced  into  the  circulation.  Thus, 
as  Ruffer  points  out,  a  drop  of  the  culture  of  the  bacillus  pyocyaneus  in- 
oculated into  the  anterior  chamber  of  the  rabbit's  eye  leads  ordinarily 
to  a  great  migration  of  leucocytes  —  to  an  acute  purulent  inflammation. 
If,  however,  the  toxins  produced  by  this  microbe  have  previously  been 
injected  into  the  circulating  blood,  no  accumulation  of  leucocytes  follows 
inoculation  into  the  eye.  Dr.  Ruffer  has  also  extended  most  suggestively 
certain  observations  of  Roger.  Subcutaneous  or  intramiisoular  inocula- 
tion of  the  rabbit  with  the  bacillus  of  s^miptomatic  anthrax  leads  to  the 
production  of  a  local  abscess  with  extbiisive  accumulation  of  leucocytes. 
After  simultaneous  injections  of  fluid  containing  vir\ilont  bacilli  and 
their  products  into  the  vein  of  the  ear  and  the  muscles  of  the  hind  leg, 


INFLAMMA  TION 


107 


li 


Ruffer  found  the  rabbit  dead,  within  fifteon  hours,  with  a  huge  tumour 
in  the  inoculated  limb.  Here,  upon  examination,  the  muscle  fibres 
were  found  widely  separated  by  exudation  fluid,  in  which  there  had  been 
great  multiplication  of  the  bacilli ;  but  leucocytes  were  entirely  absent. 
In  both  of  these  cases  we  have  therefore  diapedesis  and  determination 
of  leucocytes  following  the  purely  local  action  of  the  toxin;  want 
of  diapedesis  and  absence  of  leucocytes  when  the  toxin  at  the  same 
time  circulates  in  the  blood  stream.  If  any  large  proportion  of  the 
leucocytes  which  find  their  way  to  a  focus  of  irritation  emerge  from  the 
blood  stream,  these  divergent  results  are  only  to  be  explained  by  some 
theory  which  is  capable  of  reconciling  the  difference  in  the  action  of  the 
leucocytes  when  they  are  circulating  in  normal  and  toxin-containing 
blood  respectively. 

Now,  the  resvdts  in  these  two  cases  are  entirely  consonant  with  what 
we  know  concerning  the  sensitiveness  and  reaction  to  stimuli  not  only 
of  unicellular  organisms,  but  also  of  the  higher  animals.  Organisms, 
whether  lowly  or  of  most  complex  development,  only  perceive  and  react 
to  alteration  in  their  environment  when  the  alteration  exceeds  a  definite 
ratio.  Thus,  as  PfefEer  has  pointed  out,  a  motile  bacterium  (the  "  B. 
termo  ")  is  attracted  towards  solutions  of  peptone  :  if  it  be  already  in  a 
peptone  solution,  in  order  for  it  to  be  attracted  towards  and  move  into 
a  more  concentrated  solution,  this  last  must  be  five  times  as  strong  as  is 
the  former.  The  only  possible  explanation  that  I  can  see  of  the  above 
observations  of  Euffer  and  Roger  is  that  the  passage  and  want  of  passage 
of  the  leucocytes  out  of  the  vessels  depends  upon  the  ratio  of  diffusible 
bacterial  products  present  in  the  blood  stream  and  in  the  tissues  respec- 
tively. Where  the  products  are  localised  at  one  focus  in  the  tissues, 
the  leucocytes  are  attracted  out  of  the  unaltered  blood,  and  there  is 
active  diapedesis  ;  where  there  was  already  a  solution  of  the  bacterial 
products  in  the  blood,  the  ratio  of  difference  between  the  percentage 
amount  of  toxin  in  blood  and  tissue  may  be  insufficient  to  stimulate  the 
leucocytes ;  no  diapedesis  then  ensues. 

As  is  well  shown  in  the  experiment  with  symptomatic  anthrax,  the 
presence  of  the  bacillus  and  its  products  in  the  circulating  blood  did  not 
prevent  inflammation  at  the  region  of  local  injection ;  inflammation  and 
exudation  were  abundantly  manifest  — there  was,  in  fact,  a  more  extensive 
exudation  than  ever.  The  irritant — that  is  to  say,  the  toxic  products 
of  the  bacilli  —  at  the  point  of  injection  was  in  no  wise  hindered  from 
exerting  effects  upon  the  fixed  cells  of  the  vessel  walls,  and  promoting 
all  the  changes  in  calibre  and  condition  of  the  walls  and  in  the  blood 
^ream  characteristic  of  inflammation.  But  with  vascular  changes,  if 
ny thing  more  prominent  than  in  the  case  where  local  inoculation  alone 
had  been  practised,  the  leucocytes  stayed  within  the  vessels :  now  the 
only  cause  to  which  we  can  attribute  this  abstention  of  the  cells  from 
emigration,  is  lack  of  attraction  —  certainly  not  lack  of  vascular  change 
or  lack  of  blood  pressure. 

Sunxmanj.  —  I  am  thus  led  to  the  following  conclusions  regarding 


o; 

ur 

es 

en 

at. 


io8 


SYSTEM  OF  MEDICINE 


the  passage  of  cells  out    of    the    blood    stream    into    an    inflamed 
area :  — 

1.  The  diapedesis  of  the  leucocytes  is,  as  the  name  implies,  an  active 
and  not  a  passive  process ;  it  is  due  to  active  amoBboid  movements  on 
the  part  of  the  cells. 

2.  The  stimulus  leading  to  diapedesis  is  that  of  positive  chemiotaxis. 
It  is  the  attraction  exerted  upon  the  leucocytes  by  the  diffusible  sub- 
stances associated  with  the  irritant. 

3.  Irritants,  if  themselves  diffusible,  or  the  diffusive  substances 
developed  while  the  irritants  are  within  the  tissues,  are  capable  of  two 
separate  actions :  one  direct  upon  the  vessel  walls,  leading  to  vascular 
changes ;  the  other  through  the  walls  upon  the  leucocytes,  whereby 
emigration  may  be  induced. 

4.  These  two  actions  need  not  (and  frequently  do  not)  manifest  them- 
selves pari  passu. 

6.  In  relation  to  diapedesis,  the  dilation  of  the  vessels,  the  altered 
rate  of  blood  stream,  the  altered  disposal  of  the  corpuscles  in  the  stream, 
and  the  modified  endothelium,  may  all  be  regarded  as  adjuvants. 

6.  The  passage  of  red  blood  corpuscles  from  the  blood-vessels  into 
the  inflamed  area  is  passive,  due  to  the  blood  pressure  and  to  lack  of  con- 
tinuity of  the  vessel  walls.  Such  lack  of  continuity  is  afforded  in  many 
instances  by  the  migration  of  the  leucocytes  through  the  walls. 


Chapter  5.  —  On  the  Part  played  by  the  Nervous  System 

If  the  vascular  changes  in  inflammation  were  due  to  reflex  influcmces 
proceeding  from  the  central  nervous  system,  and  were  in  fact  controlled 
by  the  centres  in  the  brain  and  spinal  cord  (as  has  been  held  by  the 
supporters  of  neuro-humoral  theories)  then,  in  the  first  place,  there 
should  be  a  rapid  and  almost  immediate  response  on  the  part  of  the 
vessels  of  any  region  on  the  introduction  of  an  irritant.  But  this  is 
not  by  any  means  constantly  to  be  observed.  Thus,  as  Cohnheim 
pointed  out,  if  croton  oil  be  rubbed  upon  a  rabbit's  ear  more  than  an  hour 
may  elapse  before  the  first  beginnings  of  hyperaemia  can  be  detected ; 
yet  the  inflammation  eventually  set  up  may  be  very  intense.  In  the 
second  place,  section  of  all  the  nerves  passing  to  any  region  of  the 
body  should  have  this  effect,  that  injury  in  the  region  in  question  should 
be  unaccompanied  by  the  ordinary  vascular  reaction.  But  this  is  not  the 
case.  Divide  all  the  nerves  which  supply  a  rabbit's  ear  for  example,  and 
then  injure  that  ear,  either  by  heat,  cold,  or  inoculation  of  pathogenetic 
micro-organisms,  and  inflammation  manifests  itself  with  all  the  stages 
recognisable  in  an  ear  with  intact  nerve-supply.  The  vascular  changes 
which  accompany  inflammation  can  occur  then  independently  of  any 
central  nervous  influences. 

We  can  proceed  farther,  and  state  that  regions  deprived  of  their 
nerve-supply  are  peculiarly  prone  to  inflammatory  changes.  But  this 
liability  to  inflammatory  disturbances  in  such  regions  is  not  directly  dun 


^i 


TNFLAMMA  TION 


109 


to  the  destruction  of  vaso-motor  tracts  and  the  cutting  off  of  central 
influences  from  the  vessels  of  the  part,  but  is,  it  would  seem,  immediately 
connected  with  the  loss  of  sensation.  Divide  the  ocular  branch  of  the 
fifth  nerve  of  a  rabbit,  and,  if  the  eye  be  not  protected,  ulceration  and 
necrosis  of  the  cornea  manifest  themselves  in  the  course  of  a  few  days. 
Protect  the  eye,  either  by  bringing  the  lids  together  or  by  placing  a 
shade  over  it  in  such  a  way  that  dust  and  foreign  particles  are  prevented 
from  settling  upon  the  surface,  and  no  such  ulcerative  disturbance  mani- 
fests itself.  From  this  it  is  clear  that  the  primary  cause  of  the  inflam- 
mation is  not  any  trophic  change  in  the  region,  but  is  the  lack  of  sensa- 
tion, whereby  irritant  substances  are  permitted  to  gain  a  lodgment  upon 
the  outer  surface  without  any  attempt  being  made  to  remove  them. 
That,  in  addition,  there  is  a  lowered  vitality  in  parts  deprived  of  their 
nerve-supply,  and  that  this  renders  those  parts  a  more  favourable  seat 
for  inflammatory  disturbances  is  more  than  probable;  nevertheless,  this 
would  not  seem  to  be  the  primary  cause  of  the  increased  liability  to 
inflammation.     [Fide  art.  on  "Nutritional  Eetrogressive  Changes."] 

This,  then,  in  the  first  place,  is  clearly  recognisable — that  the  vascular 
changes  accompanying  inflammation  can  occur  independently  of  central 
nervous  influences.  Hence  it  follows  that  there  must  be  a  peripheral 
nervous  mechanism  controlling  the  vessels.  It  remains,  therefore,  to 
determine  the  nature  of  this  peripheral  mechanism :  is  it  wholly  under 
the  guidance  of  peripheral  nerve  cells  situated  in  the  vessel  walls,  or 
is  it,  in  part  at  least,  idiopathic  ?  In  the  present  state  of  our  knowledge 
the  answer  to  this  question  must  be  guarded.  The  more  carefully  the 
innervation  of  the  various  regions  is  studied,  the  more  clearly  is  it 
demonstrated  that  throughout  all  the  tissues  of  the  body  there  exists 
a  wonderfully  fine  and  complicated  network  of  nerve  filaments  with 
occasional  isolated  ganglion  cells.  Yet  proof  is  wanting  that  this  system 
in  connection  with  the  vessels  is  sensorimotor.  Indeed,  so  far  as  regards 
the  heart  and  ventricular  muscle  (which  may  be  looked  upon  as  the 
region  of  the  vascular  system  wherein  the  motile  portion  of  the  walls 
has  become  specially  developed),  the  researches  of  Romberg  and  His  lead 
rather  to  the  conclusion  that  the  peripheral  nervous  system  subserves 
sensation  alone. 

Dr.  H.  J.  Berkley's  careful  series  of  researches  recently  brought 
together  in  a  Johns  Hopkins  Hospital  Report  (Neurology  II.,  1894) 
throws  much  light  upon  the  termination  of  the  nerves  in  various  organs, 
and  upon  the  relation  of  these  nerves  to  the  vessel  walls.  Berkley 
finds  in  connection  with  the  ventricular  muscles  a  dense  network  of  nerve 
filaments,  with  small  bulbous  terminations  upon  the  individual  fibres. 
These  observations,  it  must  be  admitted,  tend  to  weaken  the  belief  in  the 
idiomuscular,  or,  more  truly,  idioneural  action  of  the  heart  muscle. 

At  the  same  time,  the  more  the  activity  of  the  various  tissues  is 
studied,  the  more  fully  it  is  seen  that  many  cells  retain  what  may  be 
termed  reminiscences  of  an  earlier  and  more  embryonic  condition  in 
which  their  functions  were  varied  and  less  specialised.     There  is  an 


1 109 


no 


SYSTEM  OF  MEDICINE 


inherent  probability  that  the  endothelial  cells  can  react  directly  to  stim- 
uli, and  that  they  are  capable  of  idiopathic  contraction  and  expansion 
on  appropriate  stimuli.  We  have  seen  that  these  cells  are  capable  of 
taking  up  microbes,  and  thus  seem  to  exhibit  an  independent  activity 
similar  to  that  observed  in  the  amoeba  or  the  wandering  phagocyte.  If 
these  cells,  then,  are  capable  of  throwing  out  pseudopodia,  and  thus  of 
enclosing  non-motile  bacteria,  are  they  not  capable  of  contracting  and 
expanding,  as  a  whole,  according  to  the  stimulus  of  altered  environ- 
ment ?  As  a  matter  of  fact,  such  contractility  of  the  endothelial  walls 
of  the  capillaries  has  been  demonstrated  by  Klebs  and  Severini.  I  can- 
not but  conclude,  then,  that  the  endothelium  of  the  capillaries  is  to  some 
extent  self -regulative  or  neuro-muscular.  It  is  quite  possible  —  but 
"non-proven"  —  that  the  muscular  coats  of  the  smaller  arteries  are 
likewise  capable  of  self-regulation,  and  respond  directly  to  stimuli. 

This  view — that  the  vascular  phenomena  of  inflammation  can  occui' 
independently  of  the  central  nervous  system  and  of  the  peripheral  nerves 
—  does  not  imply  that  the  nervous  system,  central  and  peripheral,  is 
without  its  influence  upon  the  process ;  far  from  it.  We  have  evidence, 
in  the  first  place,  that  the  state  of  the  vascular  walls  is  modified  after 
destruction  or  severance  of  the  nerves.  I  do  not  here  refer  only  to  the 
consequent  alterations  in  calibre  of  the  vessels,  but  also  to  the  changes 
in  other  properties.  Thus  Gergens,  and  to  a  less  extent  lltltimeyer, 
noticed  that  after  destruction  of  the  spinal  cord  the  blood-vessels  of  the 
frog  permit  a  larger  quantity  of  fluid,  and  even  particles  of  granular 
colouring  matter,  to  permeate  them. 

In  the  second  place,  we  have  evidence  that  the  central  nervous 
system  exercises  some  direct  influence  upon  the  inflammatory  process. 
From  Cohnheim  onwards  it  has  been  a  matter  of  common  observation 
that  when  all  the  nerves  of  a  part  have  been  severed,  the  stages  of  the 
process  succeed  each  other  with  greater  rapidity.  It  may  be  that  the 
modified  state  of  the  capillary  walls,  noted  in  the  preceding  paragraph, 
is  capable  of  accounting  for  this  fact,  and  that,  in  the  absence  of  central 
influences,  dilation  of  the  vessels  and  exudation  of  fluid  lead  to  the 
cardinal  symptoms  of  redness  and  swelling,  with  associated  changes  in 
the  tissue,  at  an  earlier  period. 

Of  the  part  played  by  the  different  sets  of  nerves  the  external  ear  of 
the  rabbit  again  furnishes  an  excellent  study.  This  part  has  a  double 
nerve-supply  through  the  auriculars  (major  and  minor)  passing  from 
the  cervical  plexus  and  the  sympathetic  branches  proceeding  from 
the  superior  cervical  ganglion:  stimulation  of  the  former  leads  to 
dilation  of  the  ear  vessels,  of  the  latter  to  contraction  of  the  same.  If, 
as  shown  by  Samuel,  the  sympathetics  be  divided  on  the  one  side, 
and  the  auricular  branches  upon  the  other,  the  ear  vessels  of  the 
former  side  become  widely  dilated,  and  those  of  the  latter  markedly 
constricted.  Under  these  conditions,  if  both  ears  be  subjected  to  the 
action  of  water  warmed  to  54°  C,  there  is  a  characteristic  difference  in 
their  reaction.     In  the  organ  deprived  of  sympathetic  influence  the 


INFLAMMA  TION 


III 


congestion  and  hyperemia  become  yet  more  pronounced:  an  acute 
inflammation  sets  in  which  proceeds  rapidly  to  recovery.  In  the 
opposite  ear,  with  its  constricted  vessels,  no  hyperaemia  is  set  up; 
but  there  is  stasis,  and  gangrene  may  supervene.  These  results  have 
been  confirmed  by  Eoger,  who,  taking  a  rabbit  and  dividing  the 
sympathetic  on  one  side  and  then  inoculating  both  ears  with  like 
quantities  of  a  culture  of  the  streptococcus  of  erysipelas,  found  that  the 
erysipelatous  process  manifested  itself  much  more  promptly  upon  the 
paralysed  side,  and  came  to  an  end  at  an  earlier  date.  The  reverse  was 
the  case  when  the  auriculars  of  the  one  side  had  been  divided :  here  the 
process  was  of  slower  development  than  on  the  intact  side,  and  of  slower 
course,  resulting  in  mutilation  of  the  organ.* 

The  inference  to  be  drawn  from  these  observations  is  that  section  of 
all  the  nerves  passing  to  the  rabbit's  ear  permits  the  inflammatory  process 
to  run  a  more  rapid  course ;  section  of  the  sympathetics  (vaso-constrictors) 
alone  has  the  same  effect ;  while  the  uncontrolled  action  of  the  sym- 
pathetics after  section  of  the  auriculars  (vaso-dilators)  hinders  or  prevents 
the  manifestation  of  the  ordinary  processes  of  inflammation,  and  by 
preventing  the  destruction  or  removal  of  irritant  matter  favours  necrosis 
of  the  tissues.  We  have  yet  to  learn  whether  these  results  are  capable 
of  a  general  application,  and  to  discover  how  far  they  are  borne 
out  by  clinicAl  observations  on  diverse  cases  of  localised  paralysis.  So 
far  as  they  go  they  afford  direct  evidence  of  the  power  of  the  central 
nervous  system  to  modify  the  course  of  the  inflammatory  process,  while 
they  demonstrate  admirably  how  potent  an  auxiliary  is  the  dilation  of 
the  vessels  in  the  inflammatory  process. 

Other  evidence  that  the  state  of  the  nerve^supply  of  a  region  influences 
the  manifestation  of  inflammation  is  afforded  in  sundry  neuropathies. 
In  all  of  these,  in  the  present  state  of  our  knowledge,  it  is  difficult  to 
trace  out  the  nervous  factors  associated  with  the  lesions  to  which 
I  refer.  Our  knowledge  of  the  respective  influences  of  trophic  and 
vaso-motor  nerves  is  far  too  limited  to  permit  us  to  say  more  than 
that  a  relation  exists  between  the  condition  of  the  nerve-supply 
of  the  affected  area  and  the  inflammatory  lesions  there  observable; 
that  in  a  certain  number  of  cases  inflammation  affecting  the  area  sup- 
plied by  one  branch  of  a  nerve  may  have  associated  with  it  definite 
inflammatory  disturbances  in  the  areas  supplied  by  other  branches  of 
the  same  nerve,  and  that,  similarly,  when  inflammation  affects  a  viscus, 
inflammatory  phenomena  may  be  sympathetically  developed  in  regions 
innervated  from  the  same  area  in  the  brain  or  spinal  cord.  I  have 
already  given  examples  in  support  of  the  first  statement :  the  familiar 
redness,  swelling,  heat  and  pain  of  the  side  of  the  face  which  may 
accompany  toothache  is  an  example  in  support  of  the  second,  while  the 
condition  of  labial  herpes  in  pneumonia  is  an  evidence  of  the  results  of 

1  Although  these  results  have  been  criticised  by  Samuel  aud  other  observers,  upon  re- 
viewing carefully  the  whole  literature  of  the  subject,  I  cannot  but  think  that  the  above 
paragraph  represents  the  general  trend  of  more  recent  work. 


Ill 

cute 
the 


the 
ike 
the 
the 

was 
the 

iwer 


iia 


SYSTEM  OF  MEDICINE 


the  third.  Another  example  is  to  be  found  in  the  acute  nephritis,  which 
at  times  rapidly  follows  the  passage  of  a  catheter,  or  the  impaction  of  a 
stone  in  the  urethra.  It  is  not  unlikely  that  many  of  these  sympathetic 
inflammations  are  not  direct,  but  secondary.  Thus,  the  first  noticeable 
symptom  of  catheter  fever  is  suppression  of  the  urine.  Such  suppression 
might  be  brought  about  either  by  reflex  contraction  of  the  renal 
arteries,  or,  contrariwise,  by  reflex  great  dilatation  and  congestion  of  the 
vessels  of  the  kidneys.  If  it  be  caused  by  the  former  then  the  nephritis 
can  only  be  regarded  as  secondary,  and  as  due  to  the  injury  done  to  the 
organ  by  the  stoppage  of  its  blood-supply  for  some  little  time. 

From  the  multitude  of  the  factors  involved,  these  examples,  taken 
separately,  afford  at  most  only  a  great  probability  that  the  nervous 
system  can  directly  originate  inflammatory  changes.  There  i' ,  however, 
the  clearest  proof  that  the  nervous  system  does  possess  this  power,  and 
this  is  afforded  by  the  results  of  certain  observations  upon  hypnotic 
effects.  There  are  persons  susceptible  to  hypnotic  suggestion,  in 
whom  the  suggestion  that  a  red-hot  substance  has  been  placed  apon  the 
hand  will,  in  the  course  of  a  few  minutes,  lead  to  great  reddening  of  the 
part  supposed  to  have  been  burned,  and  this  reddening  may  be  followed 
by  great  local  exudation  and  swelling — in  fact,  by  all  the  sympto'^is 
of  acute  inflammation.  Here  then  actual  inflammatory  reaction  folh  \:ih 
supposed  injury. 

It  is  unnecessary  to  do  more  than  point  out  the  light  that  this 
intervention  of  the  central  nervous  system  throws  upon  the  subject  of 
counter-irritation,  and  upon  the  modifications  of  the  course  of  inflamma- 
tions brought  about  by  idiosyncracy  of  the  individual. 

From  what  has  been  said  in  the  preceding  paragraphs,  it  foll\.)Ws 
that :  — 

1.  Acute  inflammation  in  all  its  stages  may  proceed  regularly  in  the 
absence  of  all  centrifugal  nervous  influences. 

2.  The  vessels  of  an  injured  area  are  capable  of  reacting  apart  from 
central  influences ;  it  may  be  either  directly,  or  under  the  control  of  a 
peripheral  system  of  nerve  cells. 

3.  The  central  nervous  system  is  capable  of  modiiyi  g  the  process 
of  inflammation.  It  would  appear  that  when  the  vaso-dilators  alone  are 
called  into  action  the  successive  stages  of  the  process  are  accelerated. 
When  the  vaso-constrictors  alone  are  acting  the  process  is  retarded. 

4.  Centrifugal  impulses  alone,  apart  from  any  local  injury,  may 
originate  a  succession  of  phenomena  of  inflammation  in  a  part. 

5.  Hence,  in  all  probability  a  nervous  and  central  origin  must  be 
ascribed  to  some,  at  least,  of  the  sympathetic  inflammations  seen  to  occur 
in  areas  supplied  by  the  other  branches  of  a  nerve  supplying  a  part 
primarily  inflamed ;  and  again  in  areas  supplied  from  the  same  region  of 
the  brain  or  cord  as  the  inflamed  organ. 


INFLAMMA  TION 


"3 


Chapter  6.  —  On  the  Pakt  flayed  by  the  Cells  of  the  Tissues 

As  a  consequence  of  irritation  two  opposed  processes  may  be  mani- 
fested in  the  cells  of  the  affected  area,  —  changes  leading  to  impairment 
and  death,  and  changes  leading  to  overgrowth  and  proliferation ;  de- 
generation and  regeneration. 

Either  of  these  two  processes  may,  it  is  true,  be  wholly  wanting. 
In  very  acute  suppurative  disturbances,  destruction  of  the  tissue  cells 
and  the  steps  leading  to  destruction  may  be  the  only  recognisable 
changes.  Again,  in  the  first  stage  of  most  injuries,  whether  of  me- 
chanical, chemical  or  bacterial  nature,  degenerative  changes  are  wont 
to  take  the  lead.  On  the  other  hand,  there  are  irritants  so  mild  that 
little  or  no  cell  destruction  results  from  their  action;  an  extreme 
example  of  this  category  of  inflammations  is  seen  in  those  epithelial 
overgrowths  commonly  known  as  "corns,"  due,  as  Sir  James  Paget 
pointed  out  in  his  lectures,  to  intermittent  pressure  and  irritation  of 
moderate  intensity.^  Other  examples  are  to  be  found  in  the  "  catarrhal " 
inflammations,  in  which  there  is  marked  initial  overgrowth  and  prolif- 
eration of  the  cells  of  mucous  membrane ;  and  in  tuberculosis,  again,  in 
which  characteristically  the  earliest  effects  upon  the  pre-existing  cells, 
produced  by  the  presence  and  growth  of  the  tubercle  bacilli,  are  those 
of  enlargement  and  multiplication  —  necrotic  changes,  as  a  rule,  only 
appearing  at  a  much  later  stage.  Once  more,  in  the  later  healing  stages 
of  injuries,  cell  proliferation  may  be  in  the  field  alone.  Nevertheless, 
in  a  very  great  number,  if  not  in  the  majority  of  inflammations,  the 
two  processes  may  be  found  occurring  together  —  destruction  and 
degeneration  being  in  evidence  at  the  focus  of  irritation,  and  growth 
and  proliferation  towards  the  boundary  zone,  where  the  irritant  is 
acting  in  a  less  concentrated  form. 

Although  the  two  processes  are  thus  so  frequently  associated,  it  vHll  be 
well,  for  the  orderly  review  of  our  subject,  to  consider  them  separately. 

Degeneration  of  the  Tissue  Cells.  —  Death  of  the  ])re-existing  cells 
as  an  iiumediate  conse([ucnce  of  injury  cannot  be  regarded  as  one  of  the 
phenomena  ot  the  inflammatory  process.  Immediate  death  of  the  cells 
may  be  a  result  of  injury,  and  the  disintegration  of  the  dead  cells  may 
in  itself  lead  the  way  to  all  the  symptoms  of  inflammation.    But  cessation 

*  It  may  very  well  bo  that  tlilH  Ih  not  an  cxtretno  oxnmplo.  Neoplasms  as  a  clasH, 
wliotliur  iiiaiiKiiaiit  or  iMMii^n,  not  iiiiproliiilily  tltwelop hh a c<)ii8i'<|iieiu'u  of  suinc  iiriliitioii 
liaviiiK  III)  intensity  jUNt  MiiOleiuiit  to  indiico  cell  proliforation,  aii<l  contiiuied  for  a  timo 
HutHciuntly  Ioiik  to  iinpresH  upon  the  cells  of  tlu;  nlTected  tissues  the  habit  of  ra]>i<l  multipli- 
cation. There  is  evidence  both  in  animal  and  ve>;etablo  pathology  favouring  this  rela- 
tionship between  intlainniiition  .'ind  neoplastic  growth- 

Thn  objection  may  be  raised,  with  considerable  force,  that  substances  which  lead  to 
rell-pniliferalion  ant  stimuli  and  not  irritants,  and  that  a  line  should  be  drawn  between 
intliinimation  proper  and  overgrowth  the  result  of  irritation.  I,  for  otie,  would  w  illingly 
make  this  difference,  but  while  it  is  easy  to  draw  the  liiu(  in  certain  well-nuirked  ex- 
amples, in  others,  as  I  shall  procoid  to  show,  cellular  proliferation  is  so  essential  a  purt 
uf  the  whole  inllummutory  prucuss  that  the  divisiuii  bucuuies  impussiblu. 

Vob     I  t 


»*3 


p  THE  Tissues 

!s  may  be  mani- 
to  impairment 
oliferation;  de- 

ivholly  wanting, 
the  tissue  cells 
ly  recognisable 
whether  of  me- 
anges  are  wont 
ts  so  mild  that 
n;  an  extreme 
those  epithelial 
I-  James  Paget 
nd  irritation  of 
:he  "  catarrhal " 
wth  and  prolif- 
ulosis,  again,  in 
e-exi  sting  cells, 
lacilli,  are  those 
as  a  rule,  only 
r  healing  stages 
Nevertheless, 
lammations,  the 
lestruction  and 
on,  and  growth 
the  irritant  is 

eiated,itwilll)e 
lem  separately, 
e-existing  cells 
Ml  as  one  of  the 
ath  of  the  cells 
dead  cells  may 
But  cessation 

>pla8mH  ns  n  rlnss, 
of  HoiiK'  iiriliitioii 
tinned  for  n  limo 
tnf  mpidniiiltiiilU 
voiirihK  tbiH  rulii- 

u'«'H  wliicli  load  to 
)o  ilriiwii  l)olwt*(>n 
u,  would  willihKly 
;>  woll-nmrkcd  cx- 
«>  esNunliul  II  pitrt 
lu. 


114 


SYSTEM  OF  MEDICINE 


of  action  is  not  reaction,  nor  is  failure  response,  and  throughout  this 
article  inflamiaation  has  been  considered  as  the  reaction  following 
injury,  and  tho  response  to  it.  Thus  immediate  death  of  tissue  cells  is 
resultant  and  not  reactive,  and  may  be  eliminated  from  the  category  of 
the  essential  phenomena  of  inflammation. 

The  same  is  to  some  extent  true  of  cell  degeneration,  but  not 
entirely.  While  it  is  impossible  nowadays  to  accept  Virchow's  old 
view,  that  inflammation,  is  essentially  a  process  characterised  by 
increased  nutritive  changes  in  the  cells  of  the  tissues,  it  remains  most 
probable  that  in  very  many  cases  irritation  induces  increased,  even  if 
perverted,  activity  of  certain  orders  of  cells.  The  proliferation,  swelling, 
and  more  or  less  rapid  dej feneration  of  these  cells  cannot  be  wholly 
ascribed  to  the  toxic  influence  of  the  irritant,  but  must  in  part  be 
regarded  as  a  result  of  over-stimulation  and  overwork.  This  is  most 
noticeable  in  connection  with  catarrhal  and  parenchymatous  inflam- 
mations. In  parenchymatous  nephritis,  for  example,  such  as  that  set 
up  by  cantharidin  or  septic  infection,  the  cells  especially  aifected 
are  those  whose  functions  are  especially  excretory ;  and  their  degenera- 
tion would  appear  to  be  intimately  related  to  the  performance  of  their 
functions.  Such  degeneration,  preceded  or  accompanied,  as  it  so  fre- 
quently is,  by  excessive  proliferation,  may  truly  be  regarded  as  reactive, 
and  not  as  wholly  and  primarily  destructive. 

Of  the  degenerations  which  atfect  the  tissue  cells  in  inflammation 
(and  often  at  the  same  time  the  leucocytes)  there  are  many  varieties ; 
in  fact,  according  to  the  nature  of  the  irritant,  one,  or  other,  or  all  the 
degenerations  affecting  the  tissues  in  different  pathological  conditions 
may  manifest  themselves,  save,  perhaps,  simple  atrophy  and  j)igmental 
degeneration  (as  apart  from  pigmental  infiltration).  Most  commonly 
recognised  are  cloudy  and  fatty  changes,  but  nnicoid  and  hydropic 
chau"es  are  far  more  frequent  than  is  generally  noted.  Even  so  special- 
ised :>  change  as  amyloid  degeneration  has  been  observed  occurring 
locally  in  chronic  inflammations  —  as,  for  example,  in  gummata;  while 
in  these  same  chronic  lesions  hyaline  degeneration  in  the  vessel  walls 
is  very  often  to  be  encountered. 

There  is  also  to  be  seen  in  inflammatory  disturbances  of  moderately 
acute  type  a  further  form  of  degeneration,  which  receives  a  passing 
mention  in  the  text-books,  it  is  true,  but  so  far  has  not  to  my  knowledge 
been  duly  treated  as  an  entity ;  nor  has  its  significance  been  fully  grasjied. 
This  is  what  may  be  termed  "  reversionary"  degeneration.  It  is  to  bo 
seen  affecting  tissues,  in  which  the  individual  comjMments  in  the  fully- 
formed  state  are  not  single  cells,  but  cell  complexes  or  compounds.  Such 
compoimds  are  the  voluntary  muscle  aiul  meduUatcd  n(>rve  fibres, 
and,  as  (irawitz  has  ]>ointed  out,  the  fat  cells  of  connective  tisstie.' 
These  are  formed  by  the  fusion  and  united  growth  of  several  cells ; 

1 1  horo,  and  tliroiiKhoiit  this  nrtiide,  loavo  wholly  out  of  account  (Irawit/.'s  "  Rlum- 
b«^rinf;  ctdl  "  Micory  —a  tluMiry  incapnblo  of  actual  proof,  and  at  varlnnuu  with  thu  cull 
tbuury  upuu  wbiub  is  buiiud  Ihu  uutiro  uuponttruuturu  uf  luudoru  biulu({y. 


INFLAMMA  TION 


"5 


I 


and  in  inflammation,  as  under  other  pathological  conditions,  the  de- 
generation of  the  cell-compound  as  a  whole  manifests  itself  by  a  certain 
amount  of  proliferation  of  the  nuclei  (of  the  muscle  fibre,  sheaths  of 
Schwann,  and  periphery  of  the  fat  cells  respectively),  protoplasm  can  be 
observed  to  accumulate  around  these  active  nuclei,  and  with  the  assump- 
tion by  the  component  cells  of  an  independent  existence  the  degeneration 
may  be  said  to  be  complete  —  that  is  to  say,  beyond  this  point  only  the 
shell  and  debris  of  the  original  compound  are  left  to  be  considered. 

All  these  degenerations  are  inevitably  associated  with  disturbance 
of  the  functions  of  the  affected  cells,  and  lead  to  their  death  if  the 
irritation  which  has  induced  them  be  continued.  But  death  is  not  the 
final  stage  to  be  considered.  The  ultimate  fate  of  the  necrosed  cells 
varies  according  to  the  situation  of  the  inflamed  area,  the  intensity  of 
the  irritation,  and  the  specific  character  of  the  irritant.  From  a  free 
surface  the  dead  material  may  be  freely  cast  off.  In  acute  suppurative 
inflammations,  whether  superficial  or  deep,  and,  in  general,  wherever 
there  is  an  abundant  determination  of  leucocytes,  there  obtains  a  diges- 
tion and  solution  of  the  necrosed  cells ;  and,  as  I  have  already  pointed 
out,  this  is  associated  with  the  development  of  peptones  and  albumoses, 
and  is  brought  about  largely  through  the  extracellular  action  of  the 
leucocytes.  When  there  is  a  lai'ge  area  of  cell  destruction,  with  well- 
developed  encystment  and  limitation  of  necrosis  by  granulation  tissue, 
there  the  solution  of  the  dead  material  and  subsequent  absorption  may 
be  incomplete,  and  a  fatty  debris  left  behind,  which  may  eventually 
become  infiltrated  with  lime  salts  (the  calcareous  degeneration  falsely 
so-called).  In  tuberculosis,  despite  the  presence  of  many  leucocytes  in 
the  immediate  vicinity,  the  dead  material  of  the  centre  of  the  tubercle 
undergoes  very  little  absorption,  but  remains  as  an  inspissated,  cheesy 
mass.  In  syphilis,  on  the  other  hand,  in  large  gummata,  wliile  tliero 
is  similar  death  of  the  central  cells  and  absence  of  removal,  fatty 
metamorphosis  does  not  occur  nearly  to  the  same  extent. 

Lastly,  although  very  little  is  known  about  the  subject,  attention 
must  be  drawn  to  the  fact  tliat  filong  with  the  tissue  cells  the  inter- 
cellular matrix  undergoes  modifications  r  degenerative  changes  dur- 
ing inflammation.  Among  these,  in  all  probability,  is  to  bo  clnssed  an 
increase  in  the  amount  of  intercelhihir  mucin,  a  mucoid  degeneration. 
The  inflam^natory  exudate  is  in  many  cases  rich  in  mucin,  and  althougli 
our  knowledge  of  the  changes  in  the  matrix  is  scanty,  the  fai't  that  the 
tissue  cells  in  general  show  little  evidence  of  storage  of  mticoid  or 
mucinogenous  material,  renders  it  probable  that  what  mucin  is  formed 
is  either  excreted  or  elaborated  between  the  cells.  Connective  tissue 
fibrils,  which  may  be  regarded  as  i)art  of  the  matrix,  undergo  dissocijir 
tion  and  swelling,  and  eventually,  in  acute  inflamination,  disapyiear. 
In  chronic  disturbaru^es  they  am  espc^cially  prone  to  hyaline  change. 

Ittycverdtinn  of  the  Ti'hhuc  (Mh ;  Orcrifroivth  and  l*ri>Jifvmtinn.  —  In 
the  lower  animals,  as  we  l<now,  injury  and  lu-.tual  removal  even  of  a  largo 
portion  of  the  body  may  bo  followed  by  the  complete  reproduction  uf 


n6 


SYSTEM  OF  MEDICINE 


the  lost  part.  In  man,  however,  this  reproduction  of  lost  tissue  is 
reduced  to  its  lowest  point ;  the  higher  the  tissue  the  less,  and  the 
less  perfect,  the  reproduction.  Speaking  generally,  the  tissues  which 
show  the  greatest  potentiality  for  reproduction  are  the  least  highly 
organised — those  composed  of  similar  units.  The  "connective  tissue" 
—  the  lowest  and  most  widely  distributed  —  retains  the  largest  powers 
of  proliferation  and  hyperplasia. 

In  ordinary  inflammation  hypertrophy  and  hyperplasia  of  the  con- 
nective tissue  cells  are  absent  at  the  focus  of  irritation.  Htrt  degen- 
eration is  predominant.  It  is  in  the  peripheral  zone,  away  iiom  the 
maximum  concentration  of  the  irritant,  that  (as  shown  in  case  after  case 
of  Leber's  long  series  of  studies  upon  injury  to  the  cornea),  the  con- 
nective tissue  cells  show  signs  of  enlargement  and  proliferation,  that 
tliey  become  more  swollen  and  prominent,  send  out  largo  process(!S,  and 
may  exhibit  signs  of  active  mitosis,  ^t  may  be  urged  tliat  this  peri- 
pheral change  is  not  inflammatory,  but  associated ;  yet,  as  I  have  already 
hinted,  the  signs  of  cellular  regeneration  may  manifest  themselves  at  so 
early  a  stage  that  it  is  impossible  to  disconnect  them  from  the  process 
of  inflammation.  This  fact  has  been  brought  out  with  emphasis  in 
Ranvier's  interesting  series  of  studies  on  irritation  of  the  peritoneum  by 
weak  solutions  of  caustic  substances.  If  a  few  drops  of  a  0"3  per  cent 
solution  of  silver  nitrate  bo  injected  into  the  abdominal  cavity  of  a  rab- 
bit or  guinea-pig  an  inflammation  is  set  up  which  lasts  for  some  days. 
At  the  end  of  twenty-four  hours  the  portions  of  the  serous  coat  of  the 
abdominal  contents  which  have  been  most  affected  are  found  denuded  of 
their  endothelium — the  cells  have  died  and  disappeared;  but  in  other 
regions,  less  strongly  affected,  the  endothelial  cells  present  the  reverse 
condition  of  overgrowth:  their  nuclei  are  swollen;  the  protoplasm, 
instead  of  forming  a  flattened  plate,  is  swollen,  and  presents  ^•■'ollate  pro- 
longations anastomosing  with  those  of  neighbouring  cells.  The  under- 
lying vessels  at  this  period  show  abundant  evidence  of  inflammation ; 
they  are  congested,  and  leucocytes  are  being  poured  out  into  the  mostin- 
teric  network.  Within  forty-eight  hours  there  follows  ujton  the  inflam- 
matory exudation  a  rich  devidopment  of  fine  filaments  of  fibrin,  and  ahmg 
sundry  of  these  filanumts  the  enlarged  endotiielial  cells  send  processes. 
Some  of  the  cells  become  enormous,  100/*  or  more  in  diameter.  In  this 
extension  of  the  cells  along  the  fibrinous  franunvork  wo  have  jjrobably 
the  commencing  formation  of  oricaniscd  adlicsions.  The  endotlu^lial  ('(^lls 
at  this  stage  have  become  so  nioilirH'd  from  thtfir  previous  (juicsccMit  flat- 
tened state  that  even  outside  tlu^  body  they  exhibit  amceboid  movements. 

Up  to  this  time  no  signs  of  nuclear  division  manifest,  tliemselves. 
According  toToupet,  working  lUKh'rC'ornil,  it  is  Jiot  until  the  foiirtliday 
that  mitosis  is  recognisable  in  this  form  of  inflammation,  lint  while 
iuHammatory  congestion,  exudation  of  Huid,and  (li:i])e(lesi;u)f  leucocytes 
is  proceeding  actively,  the  modified  endothelial  cells  of  the  regions  that 
have  not  undergone  the  st^verest  injury  are  with  iMjual  activity  «'ngaged 
in  what  it  is  difllcult  to  regard  as  other  than  a  re[)aratoiy  i>rocess. 


r-i 
rt 


INFLAMMA  TION 


1x7 


As  Baumgarten  showed  in  his  studies  upon  the  development  of 
tubercles,  in  the  irritation  set  up  by  the  growth  of  the  B.  tuberculosis  in 
the  tissue,  a  like  overgrowth  with  proliferation  of  the  fixed  cells  occurs 
in  the  immediate  neighbourhood  of  the  bacilli  witbo'  t  any  primary  evi- 
dence of  cell  degeneration.  It  is  true  that  of  late  the  researches  of  Borel 
have  thrown  doubt  upon  Baumgarteu's  observati(. as  lut  they  confirm 
the  earlier  researches  so  far  as  regards  the  mitosi  of  pre-existing  cells, 
and  the  absence  of  degeneration  of  these  in  the  earlier  stages  of  the 
tubercular  growth.  Borel  would  regard  all  the  large  epithelioid  cells 
of  the  tubercle  as  modifi^id  leucocytes.  For  myself  I  cannot  admit  that 
he  has  proved  this,  careful  as  his  researcihes  seem  to  be ;  and  until  the 
leucocytic  nature  of  these  cells  be  firmly  established  I  am  inclined, 
with  the  majority  ox  histologists,  to  regard  many  of  them  as  similar  in 
nature  and  origin  co  the  modified  cells  just  described  in  connection  with 
simple  inflammation. 

The  diffic'iity  of  determining  the  origin  of  the  growing  cells  in 
inflammation  has  formed  the  greatest  trial  of  the  pathologist  throughout 
an  entire  generation,  and  yet  longer ;  nor  can  we  now  assert  without 
chance  of  dispute  what  cells  are  niainly  concerned  in  the  formation  of 
new  tissue. 

When  we  examine  newly -formed  granulation  tissue  we  can  distin- 
guish cells  of  more  than  one  type  —  (1)  small  round  cells  with  poly  lobu- 
lar and  fragmented  nuclei,  (2)  other  cells  containing  oxyphil  granules,  (3) 
larger  cells  with  a  single  nucleus  and  a  relatively  large  quantity  of  proto- 
plasm, and  again  (4)  cells  of  varying  but  generally  large  size,  varying  in 
shape,  but  on  the  whole  having  the  appearance  of  spindle  colls  with  single 
oval  nucleus  and  abundant  protoplasm.    These  can  be  made  out  easily. 

The  first  two  forms  of  cells  are  clearly  leucocytes.  Further  study  of 
their  fate  shows  that  they  disappear ;  they  play  no  further  part  in  the 
organisation  of  the  tissue  save  that,  as  is  well  shown  by  Scheltema  and 
Nikiforotf,  many  of  them  are  absorbed  by  the  growing  connective  tissue 
cells,  and  thus  would  seem  to  aid  in  their  nutrition.  The  last  form 
likewise  presents,  as  such,  no  difficulties.  These  are  fibroblasts  — cells 
in  the  process  of  growth  into  connective  tissue.  But  what  is  their  rela- 
tionship to  the  previous  form,  —  to  the  round  mononucleated  cells  with 
fairly  abundant  protoplasm,  —  what  are  these  last,  and  what  in  short 
is  the  origin  of  the  fibroblasts,  —  is  it  from  leucocytes  or  from  pre- 
existing connective  tissue  cells?  Upon  this  most  difficult  question 
more  ingenuity  and  more  rest^arch  have  been  expended  than  upon  any 
other  part  of  this  well-worked  field  of  inflammation. 

There  can  be  no  doubt  nowadays  that  a  large  proportion  of  the  fibro- 
blasts in  g  "anulation  tissue  are  developed  from  pre-existing  connective 
tissue  cells.  The  genei\il  consensus  of  recent  researches  leads  de- 
cidedly in  this  diriH'tion ;  and  it  is  from  the  laboratory  of  Ziegler,  who 
by  lus  classical  observations  hul  pathologist;:  for  some  years  to  hold  the 
contrary  view,  that  th(!  studies  have  emanated  which  '>iosi.  conclusively 
sh  jw  the  part  played  by  the  connective  tissue ;  the  researches  of  KrafTt, 


Ii8 


SYSTEM  OF  MEDICINE 


Podwyssozki,  Coen,  Fischer,  and  Nikiforoff,  confirmed  and  strengthened 
by  the  researches  of  Arnold,  Marchand,  lieinke,  and  Sherringtou,  all 
bring  forward  evidence  in  one  direction.  It  is  the  clearly  recognisable 
pre-existing  cells  of  the  tissue  —  connective,  endothelial  and  epithelial 
—  which  show  most  constantly  the  signs  of  nuclear  division:  every 
stage  of  enlargement,  mitosis  and  cell  division,  can  be  made  out  in 
them.  Even  if  we  did  not  possess  the  information  afforded  by  nuclear 
changes,  the  fact  that  new  tissue  is  always  developed  in  the  immediate 
neighbourhood  of  pre-existing  tissue  would  in  itself  point  strongly  to 
this  same  conclusion. 

We  may  rest  assured  of  this  much.  But  can  we  advance  farther, 
and  state  that  all  newly-formed  connective  tissue  cells  originate  from 
the  pre-existing  cells  of  the  tissue,  and  that  none  of  them  are  derived 
from  wandering  cells  ?  In  tlie  present  state  of  our  knowledge  the 
answer  to  this  (question  must  be  an  unhesitating  "  Ko."  If  we  base 
our  observations  upon  the  morphology  of  the  cells  in  granulation  tissue, 
we  find  that  with  our  present  methods  the  large,  round,  mononuclear 
cells  seen  therein  are  undistinguishable  on  the  one  hand  from  large 
hyaline  leucocytes,  on  the  other  from  one  stage  in  the  development  of 
fibroblasts.  If  we  examine  into  their  properties  we  find  that  they  act 
as  pliagocytes  incorporating  the  multinuclcar  leucocytes.  The  fibro- 
blasts, according  to  Nikiforoff's  careful  studies,  have  an  identical  action ; 
so  also,  according  to  Metsv^hnikoff,  Kuffer,  ]*>orel,  and  others,  have  the 
large  mononuclear  hyaline  leucocytes.  If  Ave  study  their  mode  of  divi- 
sion they,  like  the  connective  tissue  cells,  exhibit  indirect  or  nuclear 
division.  It  may  be  (as  has  been  more  than  once  suggested)  that  the 
large  mononuclear  hyaline  leucoiiytes  differ  from  the  other  forms  in 
being  of  endothelial  origin.  Were  this  so  a  path  would  be  found  oiit  of 
our  present  difficulty.  Certainly  the  most  that  can  now  be  said  is  that  it 
is  quite  ]wssible  that  among  the  higher  animals  this  one  form  of  wan- 
dering cell  may  be  contributory  to  new  fibrous  tissue  formation,  quite 
possible  that  the  connective  tissue  cells  which  develop  as  a  result  of  in- 
fiammation  are  not  all  derived  from  the  pre-existing  cells  of  the  region.* 

It  must  be  borne  in  mind  that  leucocytes,  endf»thelial,  and  connective 
tissue  cells  are  very  simple  forms  of  tissue,  that  they  are  all  of  like 
mesoblastic  origin,  and  < iius  being  homogeneous,  may  be  more  variously 
modified,  without  imjiairment  of  activity,  than  more  highly  specialised 
cells.  I  must  hcie  add  that  in  lower  forms  —  in  the  tadpole's  tail, 
for  examj^le  —  Metschnikoft"  has  followed  day  by  day  the  transition  from 
leucocyte  into  typical  (»inu'ctivo  tifauo  cell,  and  that,  largely  in  conse- 
quence of  these  oljsorvations,  Fren'.;h  pathologists  hold  the  view  that  the 
leucocytes  enter  fai  more  actively  into  new  tissue  formation  than  I  hero 
recognise.     The  German  school,  with  the  exception  of  Arnold  (whoso 


1  In  this  connection  may  be  mentioned  fho  observntions  of  IVfptschnikofT,  confirmed 
l)y  Barfurth,  and  more  recently  l»y  Dr.  .Joseph  (IrldlthH,  which  show  that  in  the  dcnenor- 
alion  and  disintegration  of  miisclo  flhrcs  (of  the  tadpole's  tail)  the  proliferated  nnclei  of 
the  fibres  become  the  nuclei  of  individual  wandering  colls  — leucocytes. 


ri'i 


ki 


\m\: 


INFLAMMA  TION 


119 


views  correspond  on  the  whole  with  my  own),  has  with  Ziegler  passed 
over  to  the  opposite  camp  of  connective  tissue  only  from  connective 
tissue.  For  myself  I  have  carefully  sifted  the  evidence  adduced  by 
either  side.  What  is  said  above  gives,  I  believe,  thfi  estimate  of  the 
matter  for  the  time  being;  while  what  follows  gives  in  brief  the  state 
of  our  knowledge  of  the  part  played  in  intlamiuation  by  the  tissue  cells 
in  general. 

(1)  Two  series  of  changes  may  occur  in  the  cells  of  an  inflamed  tissue, 
which  may  be  included  under  the  terms  degeneration  and  regeneration 
respectively. 

(2)  The  extent  to  which  one  or  other  of  these  series  of  changes  pre- 
dominates varies  with  the  nature  and  intensity  of  the  irritart. 

(3)  Degeneration  and  death  of  the  tissue  cells  may  be  a  direct  and 
immediate  result  of  the  pieseuco  of  the  irritant,  and  then  can  scarcely 
be  regarded  as  essential  phenomena  ot  inflammation.  Or  they  may  be 
of  more  gradual  onset,  associated  with  evidexHC;  of  ovoi -stimulation  and 
increased  activity  of  the  cells. 

(4)  Fatty,  cloudy,  hydropic  and  mucoid  cire  the  most  frequent  forms 
of  degeneration  affecting  the  tissue  cells  iu  acute  inflammation;  hyaline 
in  chronic;  other  forms  are  rare. 

(5)  The  ultimate  fate  of  the  necrosed  cells  varies  as  the  situation, 
intensity  of  irritant,  and  specific  character  of  irritant. 

(6)  Cell-proliferation  is  so  constant  an  accompaniment  of  certain 
forms  of  inflammiit  ion  that  it  is  impossible  to  regard  this  as  an  adjunct 
and  not  as  an  essential  part  of  the  process. 

(7)  The  tissues  wiiieh  show  the  greatest  potentiality  for  reproduc- 
tion in  consequence  of  inflammation  are  those  which  are  least  highly 
organised. 

(8)  The  origin  of  fibroblasts  and  new  connective  tissue  cells  cannot 
be  regarded  as  entirely  determined,  but  this  much  would  seem  to  bo 
clearly  demonstrate  1 :  (a)  That  a  large  proportion  of  the  fibroblasts  are 
derived  from  pre-existing  connective  tissue  cells.  {&)  That  in  lower 
forms — as,  for  example,  the  tadpole  —  leucocytes  can  be  seen  to  develop 
into  connective  tissue  cells,  (y)  It  is  quite  possible,  indeed  probable, 
that  in  the  higher  animals  one  form  of  wandering  cell,  the  large  hyaline 
mononuclear,  contributes  to  the  formation  of  new  fibrous  tissue. 

Chapter  7.  —  On  Fibrous  Hyperplasia  and  its  Relationship  to 

Inflammation 

The  succession  of  change*  from  embryonic  cells  to  fully-formed  tis- 
sue can  best  be  studied  in  cases  where  there  has  been  a  relatively  largo 
area  of  destruction  —  as,  for  example,  after  severe  burns,  or  excision  of 
organs  or  large  portions  of  organs ;  or  again,  where  inflammation  has 
been  of  a  chronic  character. 

If  healthy  granulation  tissue  be  examined,  the  process  of  growtli  is 
seen  to  originate  iu  the  immediate  neighbourhood  of  if  not  in  direct 


I20 


SYSTEM  OF  MEDICINE 


connection  with  the  dilated  new  capillaries.  It  is  around  these  vessels, 
formed  of  little  more  than  a  single  layer  of  cells,  that  the  fusiform  fibro- 
blasts are  in  greatest  abundance.  At  a  later  stage,  in  regions  more  remote 
from  the  advancing  margin  of  the  granulations,  the  fibroblasts  have  a  more 
j^'eueral  distribution  in  the  intercapillary  spaces,  and  are  more  elongated ; 
{iiound  them  may  be  seen  the  earliest  wavy  fibres  of  white  connective 
t  ;-3ue.  These  are  essentially  of  cellular  origin  —  as  much  so  as  is  the 
substance  of  striated  muscle  fibres.  The  elongated  fibroblasts  not  only 
break  or  extend  at  their  poles  into  fine  processes,  but  also  along  their 
sides  the  protoplasm  undergoes  modification  into  fine  parallel  fibrillse. 
With  the  continuance  of  this  change  the  cells  become  smaller  and 
smaller  until  little  is  left  but  the  attenuated  nuclei,  often  so  flattened 
and  narrow  as  to  be  scarcely  recognisable.  It  is  generally  accepted 
that  the  fibrillar  substance  contracts  with  increasing  age ;  certainly  the 
newly-formed  cicatricial  tissue  diminishes  greatly  in  volume,  and  with 
this  diminution  the  previous  great  vascularity  of  the  part  disappears ;  the 
capillaries  shrink  until  the  majority  become  completely  occluded.  Thus 
in  place  of  the  abundant,  soft  and  succulent  granulation  tissue,  rich  in 
cells,  blood-vessels  and  exuded  fluid,  there  is  eventually  a  firm,  shrunken, 
anaemic  mass  of  fibrous  tissue,  with  rare  flattened  nuclei,  rich  only  in 
closely-pressed  bundles  of  white,  semi-transparent  fibrils. 

Fibrous  hyperplasia  is  to  be  encountered  in  almost  every  tissue  of 
the  body  as  a  sequence  of  very  diverse  morbid  conditions.  To  speak  of 
it  in  any  case  as  "  fibroid  degeneration  "  is  a  misnomer.  The  overgrowth 
of  any  tissue,  however  lowly,  is  not  a  degeneration.  Fibn  is  tissue  may 
and  often  does  become  the  seat  of  degenerative  processes,  .  ttably  the 
hyaline;  but  that  is  another  matter.  To  regard  every  condition  of 
generalised  or  localised  fibroid  change  of  the  organs  of  the  body  as  a 
chronic  "  — itis  "  is  equally  erroneous,  until  we  have  proof  absolute  that 
connective  tissue  only  undergoes  excessive  growth  directly  or  indirectly 
under  the  stimulus  of  injury.  It  is  interesting  to  note  the  opposed 
tendencies  of  the  two  branches  of  our  profession  on  this  subject; 
the  surgeons  strive  to  restrict  the  idea  of  inflammation  to  acute  pyogenic 
disturbance,  the  physicians  to  extend  the  idea  so  as  to  include  all 
cases  of  chronic  progressive  "  fibrosis."  I  will  not  say  that  the  latter 
is  as  untenable  a  position  as  the  former,  for  it  is  a  matter  of  peculiar 
difficulty  and  delicacy  to  state  what  is  and  what  is  not  an  inflamma- 
tory fibrosis;  after  all,  there  is  more  danger  of  being  tossed  about 
helplessly  in  the  Charybdis  of  including  too  little,  than  there  is  oi 
striking  upon  the  Scylla  of  including  too  much  in  our  idea  of  inflam- 
mation. 

Here  I  wish  to  point  out  how  divergent  are  the  conditions  which 
lead  to  fibroid  hyperplasia,  and  to  draw  attention  to  the  fact  that  there 
is  reasonable  ground  for  not  classing  all  forms  under  the  one  common 
heading,  even  thougli  the  resulting  appearances  maj?^  be  undistinguish- 
able  ancl  the  effects  the  same. 

Cicatricial  fibrosis  presents  little  difficulty ;  it  is  plainly  the  result  of 


i 


INFLAMMA  TION 


121 


inflammation ;  so  too  is  the  fibrous  overgrowth  upon  chronically  inflamed 
serous  surfaces.  Capsular  fibrosis  is  clearly  of  the  same  nature ;  it  is 
to  be  seen  around  foreign  bodies,  around  chronic  abscesses,  in  the 
walls  of  tubercular  cavities,  and  encapsulating  tubercles,  gummata,  and 
other  neoplasms  inflammatory  and  non-inflammatory.  Allied  to  these 
is  the  fibroid  replacement  in  old  infarcts  (including  that  following 
upon  "  myomalacia  "  cordis).  Here,  studying  a  series  of  cases,  it  can  be 
made  out  that  the  necrosed  material  becomes  surrounded  by  a  zone 
of  inflammation,  and  that,  with  the  passage  of  leucocytes  into  the 
dead  area  and  absorption  of  the  effete  material,  there  is  soon  manifest 
a  new  connective  tissue  overgrowth  advancing  inwards  from  the  pe:i- 
phery. 

Among  the  generalised  scleroses  there  is  one  form  frequently  encoun- 
tered which  may,  without  hesitation,  be  regarded  as  the  accompaniment 
of  inflammation.  This  is  seen  well  in  the  general  interstitial  nephritis 
accompanying  subacute  and  chronic  parenchymatous  inflammation  of  the 
kidney.  Of  similar  nature  are  some  forms  at  least  of  hepatic  cirrhosis, 
diffuse  syphilitic  cirrhosis,  the  diffuse  tubercular  cirrhosis  to  which  at- 
tention has  more  especially  been  drawn  by  French  pathologists,  and  an 
extensive  pericellular  cirrhosis  in  cattle,  which  I  have  of  late  been 
engaged  in  studying,  due,  it  would  seem,  to  the  abundant  multiplication 
of  a  diplobacillus  in  the  bile  capillaries  and  liver  substance.  Whatever 
be  the  immediate  cause  of  other  forms  of  cirrhosis,  overgrowths  of  fibrous 
tissue  would  appear  in  these  to  precede  atrophy  of  the  liver  cells,  and 
to  be  associated  with  the  presence  of  an  irritant. 

But  there  are  other  varieties  of  fibroid  growth  concerning  which  it 
is  less  easy  to  arrive  at  a  just  conclusion.  First  may  be  mentioned  the 
replacement  or  compensatory  fibroses.  An  excellent  example  of  this  is 
to  be  seen  in  the  sclerosis  of  well-defined  tracts  of  the  spinal  cord  follow- 
ing destruction  of  the  ganglion  cells  governing  those  tracts,  or  sections 
of  the  fibres,  at  a  point  proximal  to  their  trophic  cells. 

The  fibrosis  in  these  cases  is  not  secondary  to  a  progressive  inflam- 
mation, but  to  a  simple  atrophy  of  the  nerve  fibres.  These  shrink,  and 
their  place  is  taken  by  fibrous  tissue.  Another  equally  instructive 
example  is  to  be  found  in  the  dystrophic  sclerosis  of  the  cardiac 
muscle  fibres  to  which  attention  has  been  called,  more  especiaU  y  by 
Drs.  Martin  and  Huchard.  This  occurs  in  certain  cases  of  arterio- 
sclerosis, and  is  best  seen  in  the  papillary  muscles,  the  fibroid  change 
occurring,  not  around  the  thickened  arterioles,  but  at  the  periphery  of 
the  area  supplied  by  each.  The  muscle  fib''"s  around  the  arterioles  are 
healthy ;  but  farther  away,  through  lack  ot  nutrition,  they  have  atro- 
phied, and  their  place  is  taken  by  a  zone  of  fibrous  tissue  which  fre- 
quently manifests  hyaline  degeneration.  In  this  instance  the  morbid 
condition  of  the  arteries  is  in  itself  a  hindrance  to  active  dilatation  of 
the  vessels,  and  the  exhibition  of  the  ordinary  accompaniments  of  in- 
flammation. Indeed  this  peripheral  zone  is  singularly  free  from  leu- 
cocytes, yet  well-marked  sclerosis  appears  nevertheless. 


122 


SYSTEM  OF  MEDICINE 


Id 

IS 

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Id 
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A 


Can  these  be  regarded  as  cases  of  inflammatory  fibrous  hyperplasia? 
According  to  our  definition  they  may :  the  fibrosis  ensues  as  a  reaction  to 
injury.  It  is  legitimate  to  conceive  that  the  dying  and  atrophic  tissue 
elements  here,  as  in  the  grosser  condition  of  infarct,  act  as  irritants. 
But,  on  the  other  hand,  the  only  recognisable  evidence  of  inflamma- 
tion is  this  very  extension  of  cicatricial  tissue ;  and  even  this  is  strictly 
limited  in  amount,  being  just  sufficient  to  replace  the  dead  tissue,  and 
nothing  more. 

Active  hyperaemia  is  not  a  prominent  characteristic  of  any  stage  in 
the  first  instance  cited  above,  and  is  throughout  absent  in  the  second. 
Still,  as  I  showed  in  an  earlier  portion  of  this  article  when  treating 
of  injuries  to  non-vascular  areas,  active  hyperaemia  is  not  absolutely 
indispensable. 

Active  hyperaemia  is  entirely  wanting  in  yet  another  form  of  fibrosis 
—  that  resulting  from  passive  congestion,  whether  of  the  blood  (as  in 
clubbed  fingers,  in  that  variety  of  cirrhosis  of  the  liver  which  may 
result  from  obstructive  lung  or  heart  disease,  and  in  the  spleen  of 
portal  obstruction),  or  of  the  lymph  (as  in  chronic  oedema,  sclerema, 
elephantiasis  and  macroglossia).  Is  this  to  be  regarded  as  an  inflam- 
matory fibrosis  ?  Everything  points  to  the  conclusion  that  connective 
tissue  cells  and  their  progenitors,  like  the  Chinaman  and  the  Polish  Jew, 
can  thrive  and  multiply  upon  a  pabulum  which  is  starvation  to  those 
of  a  higher  standard.  Iq  passive  congestion,  as  in  obstruction  to 
the  onward  flow  of  lymph,  there  results  undoubtedly  a  bathing 
of  the  tissues  with  increased  lymph.  Can  this  alone  account  for  the 
hyperplasia,  or  must  we  invoke  the  aid  of  the  irritation  or  stimulus 
of  retained  effete  matters  contained  in  the  lymph?  This  question  is 
one  that  is  most  difficult  to  answer.  Underlying  it  are  the  further  ques- 
tions whether  one  broad  explanation  can  be  found  to  apply  to  all  cases 
of  tissue  hyperplasia ;  and  whether  cell  growth  in  general,  under  physio- 
logical as  under  pathological  conditions,  is  due  to  increased  nutrition,  or 
to  stimulation  of  the  cells,  to  increased  physiological  activity  of  the 
same,  or  to  removal  of  pressure  and  other  conditions  preventing  growth, 
or  to  a  combination  of  all,  or  nearly  all  of  these.  This  last  question  at 
present  remains  unanswered.  In  the  examples  before  us  of  hyperplasia 
following  passive  congestion,  one  possible  factor,  that  of  removal  of 
pressure  from  the  cells,  is  absent ;  and  we  are  narrowed  down,  I  think, 
to  two  of  the  possible  factors  named  above — relatively  increased  nu- 
trition, and  stimulation  by  effete  matters.  If  it  were  shown  that  there 
are  states  in  which  stimulation  or  irritation  by  effete  matters  plays  no 
part  in  the  overgrowth  of  new  connective  tissue,  then  we  could,  I  think, 
safely  declare  that  forms  of  fibrous  hyperplasia  exist  which  cannot  como 
under  the  heading  of  inflammatory  fibrosis,  and  that  the  fibrosis  ol 
passive  congestion  may  be  included  among  them. 

Now  such  conditions  do  exist.  That  increased  nutrition  alone  can  lead 
to  hypertrophy  of  the  tissues  was  established  long  ago  by  Hunter's  classi- 
cal  experiment  of  transplanting  the  cock's  spur  on  to  the  cock's  comb,  — > 


INFLAMMA  TION 


13} 


moving  it  from  a  slightly  vascular  to  a  richly  vascular  region.  In  the 
ensuing  overgrowth  there  can  here  be  no  question  of  irritation  by  any- 
thing beyond  the  normal  blood.^  And  passing  from  the  general  to  the 
particular,  we  have  evidence  that  there  is  such  a  condition  as  fibrous 
hyperplasia  due,  as  it  would  seem,  to  increased  nutrition  unassociated 
with  the  presence  of  toxins  or  other  cellular  irritants.  In  his  wonder- 
fully painstaking  series  of  observations  upon  arterial  changes,  Thomas 
has  adduced  two  cases  which  he  describes,  no  doubt,  as  examples 
of  endarteritis,  but  in  which  the  inflammation  is  not  apparent, 
nor  indeed  any  factor  other  than  altered  tension  of  the  arterial 
walls  leading  to  altered  conditions  of  nutrition.  He  shows  that 
immediately  after  birth  there  is  developed  a  thickening  of  the  intima 
— a  connective  tissue  proliferation  immediately  below  the  endothelium 
—  of  that  portion  of  the  aorta  lying  between  the  ductus  Botalli  and 
the  passing  off  of  the  umbilical  arteries.  During  later  foetal  life  the 
umbilical  arteries  are  the  largest  branches  of  the  aorta ;  and,  when  the 
circvdation  through  them  is  arrested,  the  aorta  above  is  too  large  for 
the  amount  of  blood  requisite  for  the  abdominal  viscera  and  the  lower 
extremities.  The  arterial  current  becomes  therefore  relatively  sh-wed, 
and  presumably,  judging  by  the  analogy  of  what  occurs  in  the  adult 
when  large  branches  of  the  aorta  are  ligatured,  the  aortic  blood  pressure 
is  for  a  time  raised.  With  this  slowing  and  increased  pressure  there 
appears  a  compensatory  overgrowth  of  the  intima  leading  to  contrac- 
tion of  the  vessel  and  its  lumen.  Generally  speaking,  when  the  area 
of  distribution  of  an  artery  is  diminished,  as,  for  example,  when 
a  limb  is  amputated,  the  artery  shows  a  similar  proliferation  of  the 
intima.  In  both  cases  the  blood  remains  healthy,  and  the  intima 
has  undergone  no  injury;  the  only  recognisable  change  has  been  a 
slowing  of  the  blood  stream,  and  probably  increased  blood  pressure; 
and  as  the  intima  is  nourished,  not  through  the  vasa  vasorum,  but 
directly  from  the  main  arterial  fluid,  it  would  appear  that  with  the 
slowing  an  increased  nutrition  is  brought  into  action.  I  can  see  no  satis- 
factory reason  for  calling  either  of  these  cases  an  endarteritis.  It  is  quite 
possible  that  other  cases  of  thickening  of  the  intima  are  due  not  to  irrita- 
tion, but  to  increased  nutrition  brought  about  by  heightened  arterial 
tension.  The  difficulty  urged  by  Councilman  that  high  arterial  pressure 
does  not  invariably  lead  to  overgrowth  of  the  intima  is  not,  in  my 
opinion,  insuperable.  It  must  suffice  if  here  I  point  out  that  it  is  more 
than  probable  that  certain  cases  of  endarteritis  are  in  no  sense  of  inflam- 
matory origin,  or  secondary  to  degenerative  changes ;  but  are  primarily 
associated  with  nutritional  changes.  In  this  connection  it  was  shown 
by  Prof.  Roy  and  myself  that  when  the  aorta  of  the  dog  is  suddenly 
and  greatly  contricted,  and  as  a  consequence  the  pressure  in  the 


(* 


1 1  here  leave  out  of  account  a  factor  which  may  bo  important,  but  about  which  wo 
know  practically  nothing  —  namely,  the  effect  of  altered  innervation.  I  am  forced  to 
assume,  perhaps  wrongfully,  that,  as  this  factor  plays  a  like  part  in  all  the  cases  und:..- 
consideration,  it  may  for  present  purposes  bo  disregarded. 


124 


SYSTEM  OF  MEDICINE 


proximal  portion  of  the  vessel  greatly  increased,  the  plasma  of  the 
blood  is  forced  into  the  cusps  of  the  aortic  valves,  and  vesicles  of  lymph 
make  their  appearance  on  the  under  surface  in  that  region  where  fibroid 
thickening  is  most  frequent  in  cases  of  chronic  high  arterial  pressure. 

Thus,  to  express  briefly  the  distinction  that  I  would  draw  between 
inflammatory  and  non-inflammatory  fibrous  hyperplasia,  I  would  say  that 
where  local  injury  leads  to  increased  nutrition  of  the  connective  tissue, 
with  increased  functional  activity  of  the  cells,  the  ensuing  fibrous  hyper- 
plasia is  to  be  regarded  as  of  inflammatory  origin ;  where,  on  the  other 
hand,  local  injury  is  not  recognisable  as  the  primary  cause  of  the  cell 
growth,  the  hyperplasia  must  be  held  to  be  non-inflammatory.  In  pas- 
sive congestion,  obstructed  lymph-flow,  and  increased  nutrition  conse- 
quent upon  arterial  change,  as  in  the  cases  cited  above,  we  can  so  far 
see  no  cause  for  the  fibrous  hyperplasia  beyond  altered  conditions  of 
nutrition ;  there  has  been  no  primary  lesion  in  the  affected  regions  induc- 
ing the  reaction.     Such  cases  must  be  considered  as  non-inflammatory. 

But  while  I  lay  down  this  distinction,  I  must  impress  upon  the 
reader  that  the  last  word  has  by  no  means  been  said  upon  this  matter, 
and  that  further  research  may  cause  a  radical  reconstruction  of  our 
opinions. 


Forms  of  Fibrous  Hyperplasia 


A.  Of  Inflammatory  Origin. 


1.  Cicatricial. 

2.  Perivisceral. 

Localised      ■!  3-  Capsular. 

4.  Replacement  — 
Gross  (of  infarcts,  etc.). 
Fine  (dystrophic;  scle.'osis,  etc.). 

5.  Cirrhotic,  associated  vy;*^^>  parenchymatous 
Generalised  {  intlammation,  interstitial  and  lymphan- 

gitic. 

B.  Of  Non-Inflammatory  Origin. 

1.  Hyperplasia  of  increased  (arterial)  nutrition. 

2.  "  of  venous  conjjestion. 

8,  "  of  lymphatic  obstruction. 

C.  Neoplastic. 

1.  Fibromata. 


( f 


Upon  the  Increased  Temperature  of  Inflamed  Areas 

Very  little  has  of  late  been  added  to  our  knowledge  in  this  division 
of  our  subject :  what  is  to  be  said  appears  now  to  be  so  well  established 
that  I  need  do  little  more  than  state  the  main  conclusions.  The  long 
controversy  that  raged  before  these  conclusions  were  fully  accepted,  and 


1 


IN  FLAM  MA  TION 


kiH^ 


John  Hunter's  original  views  shown  to  be  in  the  main  correct,  scarcely 
comes  within  the  scope  of  this  article. 

1.  The  temperature  of  superficial  regions  is  raised,  it  may  be  several 
degrees  above  the  normal,  by  the  onset  of  inflammatory  hypersemia. 

2.  The  temperature  of  internal  organs  when  inflamed  may  be  raised 
above  the  normal,  but  undergoes  no  material  increase  beyond  that  of 
other  unaffected  internal  organs  tested  at  the  same  time. 

3.  The  rise  above  the  normal,  which  is  often  present,  is  an  indication 
of  the  febrile  state  accompanying  the  inflammation,  and  not  of  locally 
increased  heat  production. 

4.  The  increased  temperature  of  superficial  areas  when  inflamed  is 
due,  not  to  the  production  of  heat  in  the  part,  but  to  the  increased 
quantity  of  blood  passing  through  it.  When  the  congestion  is  so  great 
that  stasis  ensues  there  may  be  actual  decrease  in  the  temperature  of  the 
part. 

5.  The  maintenance  of  high  external  temperature  may  exert  a 
favourable  effect  upon  the  duration  and  progress  of  specific  inflammation. 
Thus  Filehne  has  recently  shown  that  the  course  of  experimental  erysip- 
elas in  rabbits  is  more  rapid  and  more  benign  when  they  are  kept  at  a 
high  temperature  than  at  a  low.  We  possess  no  clear  evidence  that  this 
is  due  to  the  unfavourable  effect  of  the  heightened  temperature  on  the 
growth  of  the  microbes.  Pasteur's  well-known  experiments  upon  the 
production  of  anthrax  in  fowls  (ordinarily  insusceptible  to  this  disease) 
by  lowering  their  temperature  can  be  explained  on  other  grounds.  We 
have  abundant  evidence  that  heightened  temperature  promotes  vascular 
dilation:  the  experiment  of  Filehne  may  therefore  supply  a  further 
demonstration  of  the  favourable  effects  of  dilation  of  the  vessels  and 
hyperaemia  in  the  inflammatory  process. 

6.  Low  external  temperature,  or  the  application  of  cold  to  the  surface, 
contracts  the  vessels :  hence,  upon  the  lines  of  what  has  already  been 
said,  it  would  appear  that 

(a)  It  is  calculated  to  diminish  the  amount  of  exudation. 

(6)  It  is  calculated  in  consequence  to  diminish  the  pain  associated 
with  inflammation. 

(c)  It  has  no  directly  good  effect  upon  inflammation  due  to  tho 
presence  and  growth  of  pathogenetic  micro-organisms,  but 
may  have  the  reverse  effect  of  preventing  the  fullest  reaction 
on  the  part  of  the  organism. 
Where  the  irritant  does  not  itself  grow  and  multiply,  or  present 
cumulative  action,  there  the  application  of  cold  may  not  only 
be  of  no  harm,  but  of  positive  advantage,  by  lessening  the  in- 
flammatory reaction  and  preventing  this,  where  extensive,  from 
being  itself  a  cause  of  further  injury  to  surrounding  tissues. 

The  increase  of  systemic  heat  will  be  considered  in  the  article  on 
Fever. 


(d) 


I 


ised 
It  of 

tion 
lally 

|d  is 

ised 

Ireat 

the 


126 


SYSTEM  OF  MEDICINE 


(  ' 


PART  III.  —  On  the  Vakious  Forms  of  Inflammation 
Chapter  1.  —  Classification 

The  minute  changes  which  characterise  the  process  as  it  affects  one 
or  other  organ,  and  the  various  specitic  forms  of  inflammation,  will  be 
fully  described  in  special  articles.  I  have  only  to  indicate  more  general 
causes  and  main  varieties.  To  give  a  complete  classiiication  is  impossi- 
ble unless  each  separate  tissue  be  taken  'n  order,  for  each  tissue  presents 
peculiarities  either  in  liability  to  inflamm-*"ion,  or  in  the  course  assumed 
by  the  process.  Even  to  attempt  a  classification  in  broad  outline  is 
beset  with  difficulties,  for  the  inflammatory  manifestation  varies,  not 
according  to  one  or  two  series  of  causes,  but  according  to  four  at  least ; 
the  permutations  are  thus  so  numerous,  and  the  appearances  so  varied, 
that  to  give  an  adequate  scheme  of  classification  would  require  a  diagram 
in  four  dimensions.     These  four  causes  of  variation  are  — 

A.  Nature  of  tissue  affected.  B.  Position  of  tissue  affected.  C.  In- 
tensity of  irritation,  or  more  correctly  ratio  between  resistant  powers  of 
the  organism  and  intensity  of  the  irritant.    D.  Nature  of  irritant. 

A.  Nature  of  Tissue  affected.  —  As  I  have  already  shown  in  the 
first  portion  of  this  article,  there  is  in  the  earlier  stages  of  the  process 
a  difference  in  the  reaction  of  vascvdar  and  non-vascular  tissues,  the  one 
series  exhibiting  marked  congestion  and  vascular  disturbance,  the  other 
not.  At  a  later  stage,  or  in  more  chronic  irritation,  as  new  vessels  invade 
the  non-vascular  areas,  the  changes  in  the  two  series  do  no  doubt  approxi- 
mate ;  but  in  the  earlier  stages  we  may  distinguish  between  an  ordinary 
inflammation  and  "  inflammatio  sine  inflammatione." 

The  relative  denseness  and  compactness  of  the  tissues  also  introduce 
characteristic  alterations :  a  dense  tissue,  such  as  bone,  does  not  show 
the  signs  of  reaction  to  injury  to  nearly  the  same  extent  as  does  a  loose 
tissue — such  as  the  omentum,  for  example  —  thus,  in  the  former  there 
may  be  a  process  almost  as  atypical  as  in  non-vascular  areas.  The  rigid 
framework  of  a  tissue  like  bone  prevents  great  vascular  dilatation  and 
exudation,  but  at  the  same  time  may  be  the  seat  of  great  pain  due  to 
pressure  of  the  confined  exudate  upon  the  nerve  endings.  The  loose 
connective  tissue  of  a  structure  like  the  omentum,  on  the  other  hand, 
permits  great  exudation  with  little  or  no  pain. 

The  influence  of  structure  is  well  seen  in  comparing  the  course  of  in- 
flammation affecting  cutaneous,  mucous  and  serous  surfaces  respectively. 
Where  we  have  to  deal  with  cutaneous  surfaces,  or  surfaces  formed  of 
squamous  epithelium,  there  the  increased  exudation,  and  the  resistance 
offered  by  the  layers  of  flattened  cells  to  the  free  exit  of  the  exuded 
fluid,  lead  towards  the  formation  of  vesicles  or  blisters.  In  the  case  of 
serous  surfaces,  which  form  the  walls  of  a  moist  cavity,  the  irritant, 
affecting  primarily  but  one  portion  of  the  surface,  is  very  likely  to  bo 
borne  into  the  cavity  with  the  exudate  and  to  set  up  an  inflammation 


rt:i 


INFLAMMA  TION 


127 


extending  over  a  very  large  portion  of  the  surface.  Mucous  and  cuta- 
neous surfaces,  which  are  not  thus  the  boundaries  of  cavities,  exhibit  a 
more  marked  disposition  to  the  production  of  localised  inflammation  and 
of  ulcers ;  the  superficial  layers  indeed  of  a  well-formed  epithelium  or 
mucous  membrane,  by  the  protective  powers  of  their  cells,  form  a  defence 
against  irritation  from  without:  thus  the  superficial  exudate  from  a 
region  of  local  inflammation  cannot  easily  produce  a  superficial  exten- 
sion of  the  process. 

Not  only  the  nature  of  the  tissues,  but  their  function  also,  profoundly 
affect  the  character  of  the  inflammatory  manifestation.  Thus,  excretory 
organs,  by  the  very  nature  of  their  function,  during  the  attempt  to 
remove  noxious  substances  from  the  system,  are  especially  liable  to 
generalised  parenchymatous  inflammations,  —  the  irritation  not  being 
local,  but  affecting  at  the  same  time  all  the  cells  whose  part  it  is  to 
take  up  and  excrete  the  irritant  bodies. 

B.  The  Position  of  Tissues.  —  It  is  difficult  to  consider  the  position 
and  relationship  of  tissues  as  they  affect  the  inflammatory  manifesta- 
tions, without  continually  touching  upon  their  structure.  iN'^evertheless, 
the  two,  though  very  closely  connected,  do  not  go  hand  in  hand. 

A  familiar  instance  of  modification  in  form  brought  about  ))y  position 
is  to  be  seen  in  the  result  of  suppurative  inflammation  —  in  the  develop- 
ment of  ulcerous  conditions  when  the  process  affects  free  surfaces,  of 
abscesses  when  it  attacks  deeper  tissues.  The  process  in  the  two  cases  is 
virtually  the  same :  there  is  the  same  abundant  determination  of  louco- 
cytes,  tlie  same  degeneration  of  them  into  pus.  Yet  apart  from  the 
gross  difference  in  form,  there  are  minor  differences  between  the  two. 
There  is,  for  instance,  relatively  much  more  serous  exiulatiou  from  the 
free  surface  of  an  ulcer  than  there  is  into  and  around  an  abscess.  As 
a  general  rule,  inflamed  tissues  near  a  free  surface  are  the  seat  of  more 
abundant  exudation.  Of  this  liability  for  free  surfaces  to  be  the  seat 
of  serous  inflammation  I  have  already  spoken.  The  skin,  with  its  thick 
dermal  layer,  affords  a  good  example  :  when  the  full  suppurative  stage 
is  not  reached,  inflammation  affecting  the  outermost  layers  of  the  derma 
is  most  often  of  a  vesicular  or  (edematous  character ;  when  it  affects 
the  deeper  layers  of  the  derma  the  serous  infiltration  is  less  evident. 

Yet  another  example  of  the  influence  of  position  in  modifying  form 
is  seen  in  enteric  fever.  In  this  malady,  the  lymphoid  tissue  forming 
the  Peyer's  ])atehes  becomes  the  seat  of  excessive  (H?llular  infiltration 
and  proliferation,  undergoes  necrosis,  and  is  cast  off,  leaving  the  well- 
known  ulcers.  The  lymphoid  tissue  of  the  neighbouring  mesenteric 
gland  likewise  undergoes  great  infiltration  and  enlargement,  but  necrosis 
rarely  implicates  the  whole  of  a  gland :  notwithstanding  the  previous 
extensive  inflammation,  the  glands  commonly  recover  their  normal 
ai)pearance  and  size. 

Jieyond  this  there  are  few  broad  i)rincii)le8  to  l)0  laid  down  concern- 
ing the  relationship  l)etwecn  forms  of  inHaninuiiion  and  ]iosition  that 
do  not  essentially  depend  upon  the  structure  and  functions  of  the  tissues. 


127 

d  cuta- 
chibit  a 
on  and 
lium  or 
lefence 
from  a 
exten- 


128 


SYSTEM  OF  MEDICINE 


Much  can  be  sai'l  concerning  the  intimate  connection  between  position 
and  liability  to  inflammation ;  but  this  and  the  allied  and  most  impor- 
tant subject  of  the  protective  mechanisms  of  sundry  tissues  against 
injury  are  away  from  our  present  point. 

C.  The  Relative  Intensity  of  the  Irritant  is  a  more  frequent  and 
potent  cause  of  variation.  I  have  already  in  several  places  referred  to 
tlie  ratio  between  the  resistant  powers  of  cells  and  the  intensity  or 
virulence  of  the  irritant  as  it  affects  the  inflammatory  process,  and  have 
shown  how  much  that  was  previously  vague  has  been  made  clear  by 
bacteriological  research ;  while,  at  the  same  time,  it  has  brour^ht  home 
the  truth  that  the  various  forms  of  inflammation  merge  insensibly  one 
into  the  other. 

Broadly  speaking,  it  may  be  stated,  as  a  result  of  these  studies, 
that,  cfMeris  paribus,  increased  virulence  of  any  given  microbe  or 
diminished  power  of  resistance  on  the  part  of  the  organism  or  of  the 
tissues,  leads  to  corresponding  alterations  in  the  phenomena  of  inflam- 
mation at  the  region  of  inoculation ;  and  vice  versa. 

Thus,  if  a  pathogenetic  microbe,  such  as  that  of  anthrax  or  erysipelas, 
be  greatly  attenuated,  the  effects  of  inoculation  into  the  subcutaneous 
tissues  may  be  scarcely  recognisable.  If  the  attenuation  be  not  so  extreme 
some  hyperoemia,  a  determination  of  leucocytes,  and,  relatively,  very 
little  exudation,  will  be  seen ;  and  in  the  course  of  a  day  or  two  all 
traces  of  inflammation  may  have  disappeared.  Witli  sliglitly  more 
virulent  microbes  the  migration  of  leucocyt«?s  may  be  followed  by  their 
breaking  down  and  couse(pient  abscess  formation  ;  with  further  increase 
of  intensity  of  action  the  migration  of  leucocytes  may  be  wanting, 
while  the  exudation  extends  and  the  inflammation  rai)idly  spreads  and 
leads  to  a  septictcmia.  A  like  ;ieries  of  changes  is  observable  if  the 
strength  of  virns  be  constant  and  animah  more  and  more  susceptible 
(or  less  and  less  refractory)  be  inoculated. 

The  variation  in  tubercular  lesions,  from  isolated  dense  fibroid 
masses  to  loosely  formed  cell  accumulations  and  diffuse  tubercular  in- 
flammatioji,  is  evidently  explicable  on  this  law.  Tlie  law  holds  good 
also,  not  merely  for  bacterial  produ(!ts,  but  for  other  irritants  also.  The 
eft'ectof  croton  oil  varies  with  the  strength  of  the  solution  ajjplied;  and, 
as  shown  by  Samuel,  according  to  the  condition  of  the  animal.  The 
same  is  true  of  abrin  p.nd  other  vegetable  extracits. 

Turning  to  physic, il  irritants,  while  here  the  intensity  of  the  irritant 
alone  or  almost  alone  is  called  into  play,  numerous  exami)les  can  be 
given  of  the  effects  of  V!':i;il.i()n  in  thit  one  respect  upon  the  intlamnia- 
tory  manifestation  —  effects  of  cold,  for  instance,  varying  from  chilblain 
through  inflammatory  (I'denui  to  gans^rene;  of  h(>at  varying  from 
hypenemia  through  vcsicrular  inflammation  to  (uunph'to  dcstriu'tion  of 
tissue;  and,  again,  effects  of  caustic  substances.  In  this  era  of  aseptic 
surgery  wo  may  forget  what  was  well  known  to  the  last  gcmiratiun  of 
surgeons,  that  caustic  substanct's  may  be  eniploytul  either  to  originate  a 
benign  and  reparative  inflammation  (as  in  the  case  of  indolent  idcois) ; 


Iltii 


INFLAMMA  TION 


129 


or,  in  larger  quantities  or  greater  intensity,  to  bring  about  a  state  in 
which  the  death  of  the  tissue  elements  is  far  in  excess  of  the  subsequent 
repair.  Thus  then,  according  to  the  above-mentioned  ratio,  inflamma- 
tion in  a  tissue  may  vary  by  insensible  gradations  from  a  mere  hyperuimia 
up  to  a  spreading  suppurative  or  gangrenous  process ;  and  from  a  purely 
local  manifestation  to  the  development  of  what  may  be  termed  an  in- 
flammation of  the  whole  organism. 

D.  The  Nature  of  the  Irritant.  —  It  is  clear,  then,  that  it  is  impos- 
sible to  base  a  classification  upon  the  nature  of  the  irritant :  the 
attempt  to  mark  off  sharply  the  inflammations  caused  by  mechanical 
and  chemical  noxai  from  those  produced  by  bacteria  and  tlieir  ])roducts 
must  be  given  up.  Huter's  proposition  that  suppuration  can  only  be 
induced  by  microbes  has  been  repeatedly  shown  to  be  erroneous. 
Thanks  more  especially  to  the  researches  of  Councilman,  Leber,  Grawitz 
and  de  IJary  and  Straus  (many  more  names  might  be  mentioned  in  tliis 
connection),  we  now  know  that  many  chemical  substances  are  (iapable 
of  causing  pus  formation.'  Among  these  may  be  menti(med  turpen- 
tine,  croton  oil,  mercury,  cojijier  aiul  silver  nitrate.  On  the  other 
hand,  although  this  pyogenetic  j)ropei-ty  is  not  conflned  to  microbes  and 
their  products,  yet  among  microbes  it  is  not  the  common  property  of  all. 
Some,  like  the  bacillus  of  tetanus,  never  in  themselves  induce  jius  forma- 
tion: others,  like  the  bacillus  of  tuberculosis,  lead  characteristically  to 
tissue  growth  and  the  formation  of  inflammatory  neo{)lasnis  rather  tliau 
to  pus  formation.  Even  aiuong  those  which,  like  the  micrococci,  are 
highly  pyogenetic,  the  formation  of  abscesses  only  occurs  when  there  is 
a  deflnito  relationship  between  the  virulence  of  the  microbe  and  the 
resistance  of  the  organism.  The  reverse  is  equally  true,  that  numerous 
laicrobes,  not  specially  pyogenetic,  produce  pus  under  peculiar  condi- 
tions. Thus,  the  bacillus  of  enteric  fever,  when  it  multii)lies  in  the 
middle  ear,  induces  a  suppurative  otitis,  and,  as  Dr.  ('.  F.  Martin  has 
shown,  it  is  further  capable  of  originating  a  sui)])urative  arthritis. 

Im  fact,  uiuler  varying  conditions  the  same  microbe  can  induce  very 
various  forms  of  inflammation.  Thus,  Charrin  has  shown  that  the  M. 
pyocyaneus  and  its  products  are  cajjable  of  inducing  in  out!  organ — \\w. 
kidni^y  —  ])atli()logical  conditions  so  diverse  as  acute,  chronic,  ]»arenchy- 
inatous,  interstitial  and  thrombotic  ne])hritis,  with,  in  addition,  cyst 
iormatitju  and  iiiuyloid  degeneration.^  This  same  microbe  can  induce 
acuti!  suppuration  in  the  anterior  cliamber  of  the;  eye  ;  and  wlien  inocu- 
lated into  tlu^  blood  cause  a  luemorrhagi(!  inflammation  of  the  s(^rous 
surfaces.  Hence  we  can  ])rocecd  further  and  state  that  no  strict  classi- 
flcati(m  of  inflammation  can  be  made  according  to  the  nature    of  the 

>  VVIillfl  thiN  iH  HO,  it  inuflt  bo  b()rno  in  mind  Mint  under  ordinary  conditions  tlioHo 
HuliHtiincuH  viry  riindy  net  upon  tlio  orKutilHiu  in  n  Hiato  of  HiifHcittnt  concent riition  to  lin 
])yo(;(<nlc.  Tlii.s,  wliiic  it  is  iini)ossll)lc  to  ninlio  ti  sliiirp  lino  of  ilcniiircjitioii  liclvvccii 
iiiicterial  and  chemical  irritants,  it  holds  tnu)  in  tlio  main  for  man  that  suppurative  dis- 
OUKO  is  an  indication  of  tlio  prcsonce  and  ^rowtli  of  ndcrohus, 

'' 'i'hcso  changes  arc  compai':iid(  with  the  divcrsu  cotidiliuna  of  thu  kiduey  in  thu 
liuiuan  buiuK  brought  about  by  tho  scarlatinal  viruo. 

vor..  I  S 


it  a  state  in 
e  subsequent 
io,  inliamniar 
e  hyperuiuiia 
from  a  purely 
ermed  au  iu- 

,t  it  is  impos- 

initant :  the 

)y  uieclianical 

lieir  products 

a  can  only  bo 

be   erroneous. 

jeber,  Grawitz 

itioned  in  this 

is  an   (capable 

tioned  turpen^' 

On  the   other 

)  microbes  and 

)roperty  of  all. 

.uce  ])U8  forma- 

Lcteristically  to 

nis  rather  than 

microco(!ci,  are 

s  when  there  is 

aerobe  and  the 

,  that  numerous 

peculiar  condi- 

ultiplies  in  the 

.  F.  Martin  has 

a  arthritis. 

Ban  induce  very 

own  that  the  !i. 

one  orj^an — the 

ronic,  ]tarcnchy- 

n  addition,  cyst 

robe  can  induce 

and  when  inocu- 

)n  of  the  serous 

;  no  strict  classi- 

0  nature   of  the 

iry  conditionH  thoso 
t,  (Miiircntriilimi  to  bo 
ciMiirfiiliim  linlwt'f'ii 
Llittt  HUiipiiriitivf  iliK- 

)t  Iho  kidnuy  in  tlio 


130 


SYSTEM  Of  MEDICINE 


bacterial  irritants :  it  is,  however,  possible  to  make  a  general  grouping 
of  those  affecting  nuin,  as  follows  :  — 

(i.)  Micro-organisms  characteristically  leading  to  pus  and  abscess 
formation  —  Staphylococci  and  streptococcus  pyogenes,  li.  anthracis. 

(ii.)  Those  leading  to  abundant  exudation  with  necrosis  —  B.  of 
malignant  (edema. 

(iii.)  Those  leading  to  cellular  infiltration  without  usually  causing 
abscess  formation — B.  typhi  abdominalis,  M.  gonorrhoea},  B.  diphthe- 
riai,  etc. 

(iv.)  Those  inducing  characteristically  the  development  of  inflam- 
matory neoplasms  —  B.  tuberculosis,  B.  pseudo-tuberculosis,  B.  mallei, 
Actinomyces,  Aspergillus  fumigatus. 

Similarly,  chemical  substances  may  roughly  be  grouped  into  — 

(a)  Substances  causing  so  slight  an  irritation  when  introduced  into 
the  organism  as  to  induce  cellular  overgrowtiv  only  in  their  immediate 
neighbourhood  —  such  as  bland  foreign  bodies,  bullets,  etc. ;  inhaled 
])articles  of  coal,  stone,  iron,  and  the  like,  conveyed  into  the  pulmonary 
lymphatics. 

{h)  Substances  leading  to  vesicular  inflammation,  e.g.  blistering 
agents,  su(;h  as  cantharides.  (This  result,  however,  depends  more  upon 
the  position  than  the  nature  of  irritant.) 

(f)  Substances  leading  to  cell  necrosis,  followed  by  the  formation 
of  granulation  tissue  —  caustic  agents. 

((/)  Substances  leading  to  cell  necrosis  and  suppuration,  such  as 
copper,  mercury,  mineral  acids,  etc.  (a  very  rare  result  in  man). 

Tliese  lists,  from  the  considerations  given  above,  are  uecessarily  un- 
satisfactory and  imperfect. 

Other  Considerations.  —  Among  other  factors  varying  1' '  ■  inflamma- 
tory ])r()cess  may  be  mentioned  tlie  duration  of  the  action  A  the  irri- 
tant, which  of  necessity  must  modify  the  extent  of  the  manifestations 
of  disturbance  in  the  tissues.  A  simple  aseptic  incision,  for  example, 
leads  to  a  mucli  milder  and  slighter  series  of  changes  than  (i<«  the 
prolonged  presence  and  growth  of  the  tulxu-cle  bac;i.'  .s.  Yet  while  at 
first  it  might  api)ear  an  easy  matter  to  name  case  after  case  where  the 
irritant  has  but  a  monuMitary  action,  upon  further  consideration  it  is 
found  that,  in  the  majority  of  cases  of  purely  mechanical  injury,  this 
is  not  the  case;  or,  to  express  the  matter  more  ex;ictly,  in  the  case  of 
physical  injuries,  it  is  not  the  act  of  wounding  tliat  causes  the  inflam- 
mation, but  the  daniage  inflicted  u])on  the  cells  oi'  the  tissues;  as,  to  a 
very  large  extent,  inflammation  is  set  up  by  th<'  products  of  the  injured 
and  destroyed  cells.  A  bone  may  be  suddenly  broken,  and  neverthe- 
less, even  under  the  most  favourable  circTimstances,  pain,  swelling,  and 
congestion  may  affect  the  region  of  fracture  lor  several  days.  ( )n''  or 
other  region  of  the  body  may  be  rapidly  frozen:  the  inflanuuatiou 
does  not  manifest  itself  till  after  the  physical  agent  has  cc;i.sed  to  act, 
but  it  continues  for  hours,  and  «^ven  for  days. 

There  are,  moreover,  physical  irritants  of  anothi-r  nature  pruducing 


INFLAMMA  TION 


I3» 


definitely  chronic  inflammation ;  I  refer  to  foreign  bodies  which  have 
gained  an  entrance  into  the  system.  These  if  bland  in  themselves  may 
nevertheless  cause  irritation.  A  good  example  of  the  extensive  inflam- 
mation which  such  bodies  may  set  up  is  seen  in  the  dense  fibrous  inter- 
stitial tubercular  masses  developed  in  the  lungs  of  stone-masons  around 
fine  silicious  particles  carried  int*^  she  lymphatics  from  the  alveoli. 

From  such  examples  it  will  b.  evident  that  no  satisfactory  distinc- 
tions between  bacterial  irritants  on  the  one  hand,  and  physical  irritants 
on  the  other,  can  be  founded  on  the  duration  of  irritation.  This  factor 
plays  no  easily  recognised  i)art  in  determining  the  various  forms  of  in- 
flammation, and  consequently  I  have  forborne  to  place  it  in  the  list  at 
the  beginning  of  this  chapter. 

In  thus  passing  rapidly  over  the  influence  of  each  of  the  four  main 
causes  of  variation  I  have  of  necessity  excluded  sundry  forms  of  in- 
flammation due  to  the  combined  action  of  two  or  more.  There  are,  for 
instance,  s\ich  woll-marked  forms  as  the  catarrhal  and  croupous,  due  to 
the  interaction  (^f  all  four  factors :  embolic  inflammation  and  lymphan- 
gitis have  also  been  passed  over;  these,  however,  are  not  so  much  forms 
of  inflammation  as  inflammatory  processes  occurring  in  special  regions 
as  a  result  of  s})ecial  methods  of  conveyance  of  the  irritants. 

The  factors  then  are  so  many,  and  their  interaction  so  varied,  that 
anything  approaching  to  an  orderly  classification  is  hopeless.  What  1 
have  here  written  must  be  regarded,  not  as  an  attempt  to  formulate 
such  a  classification,  but  as  an  attempt  to  indicate  briefly  how  the  nature 
and  position  of  tlie  tissues,  aiid  the  nature  and  intensity  of  the  irritant 
bring  about  modifications  in  the  process  of  inflammation. 


Chai'tkk  2.  —  On  Svstemic  Changes  Consequent  upon 

Inflammation 

The  results  of  an  acute  local  inflammatory  process  are  not  confined  to 
the  immi!(liate  locality,  but  associated  alterations  in  the  system  at  largo 
have  long  l)een  recognised;  yet  while  recognised  these  systemic  changes 
have  been  but  little  studied :  I  cannot  pass  the  matter  over  in  silence, 
but  my  setting  forth  of  it  must  necessarily  be  very  brief  and  imperfect. 

I  cannot  liere  say  more  upon  the  elfect  of  local  irritation  on  the 
nervo\is  system  than  that,  ai)art  from  direct  reflex  action  leading  to 
changes  of  nervous  origin  in  the  region  of  injury  and  the  reflexes 
affecting  ass(Muated  regions,  the  higher  centres,  an»l  through  them  the 
system  at  large,  may  become  affected  by  i)aths  that  it  is  not  always 
easy  to  trace. 

The  disturbances  of  the  nervous  system  whicli  accompany  local  inj\iry 
can  bo  but  vaguely  and  indefinitely  desi'ribed.  As  regards  tlic  serondary 
effects,  the  recent  most  suggestive  work  of  Prof.  Roy  and  Dr.  Cobhett 
upon  Shtx-k  [vn'rfc  art.  on  "Shock  "  in  a  later  volume]  indicates  that  there 
is  here  a  rich  field  for  yet  further  rcseandi.  ( )f  the  changers  in  tlie  genenil 
circulation,  and  moro  especially  in  the  eirculatin„  bh)od,  thanks  to  tlie 


132 


SYSTEM  OF  MEDICINE 


observationsf'  of  Von  Limbeck,  Rieder,  Lowitz,  and  Sherrington,  we  are 
in  possession  of  more  exact  knowledge.  On  acute  local  inttanimatiou 
of  some  extent  the  circulating  blood  becomes  inspissated;  by  exudation 
it  loses  some  of  its  plasma,  while  the  more  solid  constituents  —  the  red 
corpuscles  —  do  not  escape.  The  amount  of  fluid  lost  to  the  ciro\dation 
is  not  equalised  by  increased  entrance  of  lymph  into  the  fcirculation :  in 
one  experiment  of  Prof.  Sherrington  the  l)lood  remained  apoplasmic  (i.e. 
its  specific  gravity  remained  heightened)  for  more  than  sixty  hours  after 
the  infliction  of  injury.  This  apoplasmia  or  diminution  in  the  relative 
amount  of  plasma  in  the  blood  appears  to  depend  in  some  measure  upon 
the  extent  of  the  vascular  area  involved  in  the  inflammation ;  for  example, 
Sherrington  shows  that  when  both  feet  are  involved,  by  plungingthe  limbs 
in  water  of  52°  C,  the  apoplasmia  is  more  severe  than  in  experiments 
affecting  one  foot  only.  Another  well-marked  change  in  the  blood  concerns 
the  leucocytes.  As  suspected  by  Lowitz  and  proved  by  Sherrington,  there 
is,  in  some  forms  of  inflammation  at  least,  a  primary  dimiiuition  in  the 
number  of  leucocytes  per  unit  volume  of  blood  (leuoocyto])enia),  followed 
by  a  n-arked  increase  in  tlie  number  of  leucocytes  in  the  blood  (leuco- 
cytosis).  The  number  of  leucocytes  was  in  some  instances  increased 
sevenfold.  In  the  leucoc^topenia  of  inflammation,  the  diminution  is 
chiefly  contined  to  the  finely  granular  leiicoc^ytes — the  finely  granular 
oxyi)hile  cells  of  Kautluick  and  Hardy.  These  observations  of  Slusrring- 
ton  are  confirmed  by  the  observations  of  Everard,  Demoor,  and  Massart. 

Whetlier  the  diminution  l)e  due  to  disintegration,  or  to  collection  in 
some  area  of  the  circulation,  is  not  yet  determined.  Tlie  leucocytosis 
may  become  obvious  within  an  hour  after  the  establishment  of  a  local 
lesion ;  aiul  it  may  be  })rolonged  for  several  days,  even  in  (jases  where 
the  injury  has  been  of  a  mechanical  nature.  Here,  again,  according  to 
most  observers,  it  is  chiefly  the  polynuclear  or  finely  granular  oxyphilo 
cells  which  increase  in  niimbers.  It  is  interesting  to  note  that  coinci- 
dently  the  coarsely  granular  eosinophile  cells  appear  to  undergo  great 
diminution.  1  can  do  no  more  than  point  ovt  the  existence  of  tliose 
l)i()od  changes,  and  furtlier  that  changes  ni  the  number  of  leucocytes  in 
the  blood  are  certainly  not  accounted  for  by  the  number  passing  from 
the  blood  into  the  inflanu>d  area.  It  would  seem  that  local  inflamma- 
tion in  some  way  brings  about  an  over-stimulation  of  lymjjh  glands, 
whereby  an  increased  number  of  leucocytes  are  j)()ured  into  the  blood ; 
or  it  may  initiate  increased  proliferation  of  the  leucocytes  alnvidy  in 
the  cinndation;  but  how  one  or  other  of  these  effects  is  ])ro(luce(l  is 
at  present  unknown.  (Certainly  tlie  direct  introduction  of  the  products 
of  i)a(!terial  growth  into  the  ciicuiating  blood  may  lead  to  a  more  or  less 
pronounced  and  rapid  dimitnition  of  tlie  number  of  leucocytc^s  in  the 
blood,  and  this  diminution,  as  shown  by  Ii()witz,  may  be  preliminary 
to  a  subsequent  increase. 

The  further  important  gem^al  disturbance  associated  with  local 
injury,  more  esp*Miidly  when  of  bacterial  origin,  uainely,  tlte  occurrence 
of  fever,  will  be  desc;  ibed  in  another  artichi.     IJacteriological  studies 


INFLAMMA  TION 


nz 


lead  to  the  conclusion  that  traumatic  fever,  at  any  rate,  is  largely  due  to 
the  diffusion  in  the  blood  stream  of  soluble  bacterial  products,  and  of  the 
products  of  tissue  destruction  derived  from  the  inflammatory  focus. 


,  Chapter  3.  —  Conclusion 

In  studying  thus  the  reactions  of  the  organism  to  injury,  we 
are  impressed  by  the  multifariousness  of  natural  processes;  the  end 
may  be  attained  not  in  one  way  only  but  in  many.  "It  is  not  by 
cells  of  one  order  alonf»  -by  phagocytes  —  or  by  leucocytes  in  general 
and  only  leucocytes,  ui  icerely  by  the  reaction  on  the  part  of  the  fixed 
cells  of  the  tissue,  or  Uy  vascular  changes  alone,  or  by  altered  tempera- 
ture, or  solely  by  the  A  nical  and  mechanical  action  of  the  exudate  that 
repair  is  effecte-  \ .  Aii  /neaus  are  employed  to  antagonise  the  irritant  and 
to  effect  healin.'  '^'  c  Us  of  the  body,  fixed  and  free,  play  their  part ; 
the  nervous  sysi  Luds  the  process ;  the  bodily  humours  render  efficient 
help;  modificctUons  '  '.r  vessel  walls  and  blood  stream  are  valuable 
auxiliaries.  Divers*  ,  co-Mjsses  are  employed,  now  one  more  particularly, 
now  another,  according  to  the  needs  of  the  moment,  but  none  exclusively." 

The  time  has  come  when,  example  after  example  having  clearly  indi- 
cated the  meaning  and  the  tendency  of  that  response,  we  may  securely 
acknowledge  the  t(  ndency,  and  see  in  inflammation  not  merely  the  re- 
sponse to  injury,  b  it  the  attempt  to  repair  injury.  To  object  that  a 
definition  containing  this  statement  is  teleological  is  absurd  in  the  face  of 
fact  after  fact  that  can  be  interpreted  on  this  assumption  only.  What  is 
the  development  of  cicatricial  tissue  nut  an  attr^mpt  at  repair?  What 
other  meaning  can  be  ascribed  to  the  increased  bactericidal  power  of  the 
inflammatory  exudate  as  compared  with  that  of  ordinary  lymph  and 
blood  serum  ?  Why  do  leucocytes  accumulate  in  a  region  of  injury  ? 
Why  do  some  of  them  incorporate  bacteria  and  irritant  parti<  les,  and 
others  bring  about  the  destruction  of  these  without  necessarily  ingest- 
ing them?  All  these  are  meaiiH  wherel)y  irritiints  are  antagonised  or 
removed,  and  reparation  and  return  to  the  f»«^)rmal  sought  after. 

It  must  be  kept  in  mind  that  attempt  to  •  oair  luav  be  far  from 
repair.  Indeed,  we  frequently  find  that  the  reaction  to  injury  is  (Mspnv 
portionate  to  the  strength  of  the  irritant,  being  .  ither  insuflicieii  or  ex- 
cessive. The  exudation  may  p()ss«!ss  but  sliglit  bactericidal  powers,  (»r 
may  be  poured  out  in  such  (juantities  that  the  microbic  ii -itant,  instead 
of  being  retained  in  the  region  of  injury,  is  conveyed  outside  that  reginti ; 
the  wandering  cells  instead  of  destroying,  may  undergo  destruction ;  they 
may  incorporate  bacteria,  but  not  be  abh^  to  annihilate  tht>m ;  the  fixed 
cells  may  either  form  an  incomplete  cicatrix,  or  continue  to  ]iroliferate  in 
excess.  The  means  of  defence  on  the  part  of  the  organism  are  not  so 
much  a  preparation  in  advance  as  an  inheritance  or  an  arquirement  — 
either  a  transmission  from  those  forms  which,  being  possessed  of  the  most 
highly  developed  means  of  defence,  have  survived  wluh^  forms  with  f«'.wer 
resources  have  been  destroyed;  or,  on  the  other  liand,  an  accession  derived 


134 


SYSTEM  OF  MEDICINE 


k 


: 


from  previous  successful  resistance :  not  being  a  preparation  in  advance,  the 
reaction  to  injury  is  not  exactly  proportionate  to  any  and  every  irritant. 

But  the  mere  statement  that  inflammation  is  an  attempt  to  repair 
injury,  or  that  it  is  the  response  thereto,  is  insufficient  as  a  detini- 
tion,  for  thereby  the  general  disturbances  which  may  accompany  the 
changes  occurring  at  the  seat  of  lesion  are  included ;  these,  kowever,  may 
be  excluded  without  seriously  affecting  our  conception  of  the  process,  in 
fact  with  positive  advantage  to  a  clear  comprehension  of  the  distinction 
between  inflammation  and  fever.  And,  further,  if  what  I  have  urged  in 
the  chapter  upon  the  part  played  by  the  nervous  system  be  correct, 
account  must  be  taken  of  the  fact  that  the  leading  phenomena  associated 
with  the  inflammatory  process  may  occasionally  present  themselves  solely 
under  the  direction  of  perverted  nerve  action,  and  apart  from  actual  local 
injury. 

Hence  I  am  inclined  to  consider  that  we  can  now  pass  beyond  the 
conception  of  the  process  with  which  I  began  this  article,  and  cannot 
merely  regard  it  as  a  succession  of  changes  in  a  part  constituting  the  re- 
action to  injury,  but  can  with  propriety  acknowledge  the  purpose  of  that 
succession.  From  these  considerations  I  am  led  to  define  infla^imation 
as  the  series  of  changes  constituting  the  local  manifestation  of  the  attempt  at 
repair  of  actual  or  referred  injur n  to  apart,  or,  briefly,  as  the  local  attempt 
at  repair  of  actual  or  referred  injury. 

So  diverse  are  the  opinions  of  pathologists  upon  many  branches  of 
this  sidiject  of  inflammation,  and  so  great  is  the  amount  of  recent  research 
that  I  can  neither  hope  that  all  the  conclusions  here  set  down  will  gain 
acceptance,  nor  that  in  these  pages,  inevitably  condensed  as  they  are,  I 
have  succeeded  in  recognising  and  duly  acknowledging  all  work  of  primary 
importance.  It  is  possible  also  that,  having  been  unavoidably  prevented 
of  iate  from  seeing  and  discussing  with  others  the  results  they  have  ob- 
tained, I  may  in  some  cases  have  viewed  facts  in  a  wrong  persiicctive. 
In  the  rapid  progress  of  our  science,  much,  it  may  be,  that  is  here  set 
forth  will  be  modified.  Nevertheless  I  hold  that  the  ('onco])tion  of  the 
inflammatory  process  indicated  in  this  arti(!lc  is  that  wliich  embraces  the 
largest  number  of  like  phenomena,  and  exc^ludcs  most  satisfactorily  those 
which  if  associated  are  unessential ;  and  that  it  is  by  the  study  of  ci'llular 
pathology  in  its  strictest  sense  that  the  surest  advance  has  been  and  is 
to  be  made  in  our  knowledge  of  this  the  dominating  process  in  disease. 

JouN  Geouoe  Auami. 


SELECT  BIBLIOGi:  \PHY 

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1.  Rknnrt.  0»  Tnjfammafinii.  E<liiibnrjih,  1844.— 2.  Rir.t-noTH.  Wiener  kl in. 
Wochcnsclir.  \m2.  Nos.  1  ami  'J.  — :V  llornrAitn.  Si'tnniiio  >/«'«/.  1  Sill.  No.  L'O. — 
4.  HuitDDN-aANDKRSdV.  Unlinrx'n  Sf/Kfcm  of  Suri/iTi/,  i.  (jiivi'spxtciisivoseltict  biblioii- 
riipliy). — f).  HitRn<)N-SANi>KiiS(i\.  Crooniuii  liecdircH,  1K!)'_'.  (/(/"  I.nnrrt,  ii.  ISii'J, 
pp.  1027,  I08.'t„  114(»,  ami  1207. -- fi.  Coiinhkim.  VorloKtmiirti,  sccon.i  clition. 
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INFLAMMA  TION 


m 


7.  CoRNiL  ET  Rantibr.  MoTivel  d'Histolof/ie  pathologique,  i.  —  8.  Councilman. 
Dennis's  System  of  Surgery,  i.  1895.  — 9.  Hamilton.  Text-book  of  Pathology,  i. 
1889  (gives  extensive  bibliography).  — 10.  HUtbr.  Grundriss  der  Chb-urgie,  i. 
1883.  — 11.  Kocu.  Wunditifectionskrankheiten.  Leipzig,  1878. —  12.  Leber.  Die 
Entstehung  der  ErUzdndung,  Leipzig,  Engelmann,  1891.  — 13.  Lbtulle.  L' Inflam- 
mation. Paris,  1893.  — 14.  Mbtschnikoff.  Pathologic  compare  de  I' Inflammation. 
Paris,  Masson,  1892.  Eng.  transl.,  London,  1894.  — 15.  Neumann.  "  Uber  dem 
Entziinduiigsbegriff,"  Ziegler's  Beitr.  v.  1889,  p.  347.  — 10.  Recklinghausen. 
Handhh.  d.  allyein.  Path.  1883.  — 17.  Roser.  Entziindtmg  vnd  Heilung.  Leipzig, 
188C.  — 18.  Samuel.  Virch.  Arch.  Iv.  1872,  p.  iJSO.  — 19.  Samuel.  Die  Entzdnd- 
ungsprocess,  1873.  —  20.  Thoma.  "Ueber  Entziindung,"  Berlin  klin.  Wochenschr., 
188(5  (on  tlie  suppression  of  tlie  term  "  Inliammation  ").  —  21.  Virchow.  CellvUtr 
Pathology.  Eng.  transl.  from  second  edition  by  Chance.  London,  1860.  —  22.  Wagnkii. 
Hdbuch.  der  alluem.  Path.  Eng.  translation.  New  York,  W.  Wood,  1879  (gives  older 
literature  very  fully).  —  23.  Weigert.  "  Entziindung,"  Eulenburg'a  Realenryclopadie, 
1880,  iv.  p.  044.  —  24.  Ziegler.  Lehrbuch  der  allgemeinen  pathologische  Anatomie, 
8th  German  edition,  1894. — 25.  Ziegler.  Rede  gehalten  am  25  April  1892  zur  akademi- 
tchen  Feier,    Freiburg,  Lehmaun,  1892. 

II.  The  Comparative  Pathology  of  Inflammation 

20.  Greenwood,  Miss  M.  — J.  of  Physiol,  vii.  1880,  p.  254;  viii.  1887,  p.  263; 
xi.  1890,  p.  570;  xvi.  18S)4,  p.  441.  — 27.  Proc.  Roy.  Soc.  liv.  1893,  p.  400,  "Inter- 
cellular  Digestion."  —  28.  Hardy.  J.  of  Physiol,  xiii.  1892,  p.  105,  "Blood  Corpuscles 
of  Crustacea."  —  29.  Krukknbbrg.  Unters.  a.  d.  physiol.  Inst,  in  Heidelberg,  ii. 
1H78,  p.  273,  "  Intercellular  Digestion."  — 30.  Le  Dantec.  Ann.  de  I'Inst.  Pasteur,  iv. 
18it0,  p.  770,  and  v.  1891,  p.  103. — 31.  Loeu.  Biol.  Lectures,  Marine  Biol.  Lap., 
Wood's  Hole,  1893.  Boston,  Ginn  and  Co.,  18!»4,  p.  43.  —  32.  Metschnikoff.  A.  de 
I'Inst.  P.  iii.  1889,  and  No.  14,  gives  main  literature. — 33.  Pfkffer.  Unters.  a.  d. 
botan.  Inst,  in  Tiibingen,  vols.  i.  and  ii.  —  34.  Reinke.  Unters.  a.  d.  bot.  Inst,  in 
Gottingen,  1881.-35.  Stahl.    Botan.  Zeitung,  1884,  Nos.  10-12. 

III.  The  Steps  of  the  Inflammatory  Process  in  the  Higher  Animals 

In  addition  to  Noa.  0,  7,  8,  12,  19  and  23,  consult  — 30.  Flemming.  Virch.  Arch. 
Ivi.  1872,  p.  140,  on  "Development  of  Fibrin  in  Inflamed  Tissues." — 37.  Hess. 
Virch.  Arih.  cix.  1887.  p.  ;«>.'>.  — 38.  Hohnfeldt.  Ziegler's  Beitr.  iii.  1888,  p.  343. 
—  39.  Jacobs.  Britr.  z.  Histol.  d.  acut.  Entziindung  d.  Cornea,  Inaug.  Diss.  Bonn, 
1887.-40.  Ranvier.  t'tes.  rend.  d.  I'Acad.  d.  s'c.  1891,  April  20th,  p.  846. —  41. 
Sknftleben.  Virch.  Arrh.  Ixxii.  p.  .542.  —  A  satisfactory  bibliography  of  thi.s  sub- 
ject is  given  by  Biirdon-Sandermon.  Nos.  4  and  5.  For  full  references  to  recent  work 
upon  mycotic  inflammation  consult  Baumgarteu's  Jahrcsbericht. 

IV.  On  the  Forms  and  Varieties  of  Leucocytes 

42.  Ehrlich.  "  Farbenanalytischo  Unters.  z.  Histol.  u.  Klinik  dcs  Blutes," 
Oesnmni.  Mitthl.  Berlin,  Hirschwald,  1891.-43.  Everard,  Drmoor,  and  Massart. 
A.  dp  I' I.  P.  vi:.  1893.-44.  Gi.uge.  Observnt.  nonn.  microscop.  in  Ivflnmm.  W.Vt. — 
4.5.  (IVLLAND.  Lab.  Rep,  R.  C.  P.  Kdin.  iii.  1891,  p.  100.— 40.  Gulland.'  J.  of 
J'athii/.  ii.  1804,  p.  447.-47.  Wharton  Jones.  Phil.  Trans.  1840,  p.  04.-48. 
Kanthack.  Med.  Chron.  Now  scries,  i.  18it4,  pp.  240,  332.-49.  Kanthack  and 
Hardy.  J.  of  Pathol,  xvii.  1894,  p.  81;  and  Phil.  Trans.  1804.  — .HO.  Mf.snil. 
A.  de  I'l.  P.  ix.  1895,  May.— 51.  Metschnikoff.  B.  M.  J.  31st  Jan.  1891,  and 
No.  14.-52.  Ranvier.  "Dps  Clasmatocytes,"  (Jtes.  rend.  d.  I' Acad,  dcs  Sc.  ex. 
1«89,  p.  105. —53.  Rifder.  licitr.  z.  Kenntniss  d.  Leucocytose,  Leipzig,  1892;  and 
itlas  (I.  klin.  Microscopip  rfr.s  lilutps.  Leipzig.  1892.-54.  UiNDFLEiscir.  Pathol. 
Histohx/ip,  1801;  und  Ezptelle.  Studicn  ii.  d.  HiMohgie  dcs  Blutes.  Leipzig.  180.3.— 
55.  Max  Hchultze.  Arrh.  f.  vukr.  Anat.  i.  1803,  p.  1.-50.  SHEKRiNOTOTif.  Proc. 
Roy.  Soc.  Iv.  1893.  p.  101.  — 57.  SiAwciLLo.  A.  de  I'l.  P.  ix.  May  1895.  — For  fuller 
bibliography  consult  Nos.  40,  48,  and  53. 


136 


SYSTEM  OF  MEDICINE 


V.  On  tbb  Nature  of  Giant  Cells 

58.  BuBREL.  A.  de  I'Inst.  Pasteur,  vii.  1893,  p.  593.-59.  Dubnschmamn.  J.  of 
Pathol,  iii.  1894,  p.  118.  —60.  Fabbb,  Knud.  J.  of  Pathol,  i.  1893,  p;  349.  -61. 
Koch.  Mittheil.  a.  d.  kaiserl.  Gesundheitsamt,  ii.  18M.  —  (J2.  Lanouans.  Virch. 
Arch.  xlii.  18U8,  p.  382,  and  xlix.  1870,  p.  G6.— (J3.  Marchand,  P.  Virch.  Arch. 
xciii.  1883. — 64.  Johannes  Mulleu.  Ueber  den  feineren  Jtau  und  die  Formen  der 
Krankhaften-Geschwiilste.  Berlin,  1838. — (55.  Kibbbrt.  Der  unteryang.  pathogen. 
Schimmelpilze  im  Korner.  Bonn,  1887.-66.  Buffer.  A.  de  I'Inst.  P.  v.  1891. — 
67.  SouDAKEWiTCH.  Virch.  Arch.  cxv.  1889.-68.  Stchastny.  A.  de  I'Inst.  P. 
V.  1891,  p.  225.-69.  Vikchow.  Virch.  Arch.  xiv.  1858,  p.  47. —70.  Weiuert.  D. 
med.  Wochcnschr.  1885,  and  Virch.  Arch,  cxiii.  1889.  —  71.  Zieolbr.  Expt.  Unter- 
auch.  a.  d.  IIe7-kunft  d.  Tuhi'.rkelclemente.  Wurzburg,  1875.  —  Earlier  literature  given 
by  Mabcuand  (Nu.  63),  later  by  Faber  (No.  60). 

VI.  On  Chbmiotaxis 

72.  Councilman.  Virch.  Arch.  xcii.  1883.-73.  Gabbitchewski.  A.  de  VI.  P. 
iv.  1890,  p.  34(i.— 74.  Kanthack.  See  No.  48,  and  B.  M.  ./.,  June  18th,  1892.  — 75. 
Leber.  See  No.  12.-76.  Massart,  J.  A.  de  I'l.  P.  vi.  1892,  p. 321.— 77.  Massakt 
and  BoRDET.  J.  d.  I.  Sue.  Boy.  d.  Sc.  Med.  et  Nat.  de  Jiruxelles,  1890.  —  78.  Massart 
and  BoRDET.  A.  de  I'l.  P.  v.  1891,  p.  417.  —79.  rBKBLHARiNQ.  La  Scmaine  med.  1HH9, 
No.  22,  p.  184.-80.  Pfeiffeb.  See  No.  33.  — 81.  Stahl.  See  No.  35.— For  fuller 
bibliography  consult  Massart  and  Bordet,  No.  77. 

VII.  On  Phaqocytosis  — General  Abticlbs 

82.  Adami.  Med.  Chron.  Nov.  and  Dec.  1891.— 83.  Baumgarten.  Ctbl.  f.  klin. 
Med.  1888,  No.  26;  Zeigler's  Beitr.  vii.  1889;  Berl.  klin.  Woch.  1884,  Nos.  50  and 
51.  —  84.  Bitter.  Zeitachr.  f.  Hygiene,  iv.  1888,  p.  405.-85.  Discussion  on  Immunity 
(Roux,  Metsclinikoff,  Hankin,  Behring,  Buchner,  etc.).  Trans.  Internal,  Vongr.  of 
Hygiene,  London,  1891,  vol.  ii. — 86.  Discussion  on  Immunity.  Internal.  Vongr. 
of  Hygiene  Buda-Pesth,  1894  (Metschnikoff,  Roux,  Buchner,  Denys,  etc.),  Ctbl.  f. 
Baku  1894.  —  87.  Discussion  on  Immunity.  Path.  ISoc.  London,  1892  (Woodhead, 
Klein,  Hankin,  Martin,  etc.) ;  Path.  Trans.  1892,  v. ;  also  B.  M.  J.  of  Feb.  20  and  27, 
1892.-88.  LuBARSCH.  Fortschr.  d.  Med.  viii.  1890,  No.  17.  — 89.  Lubarsch.  Zeitschr. 
f.  klin.  Med.  xviii.  1891,  p.  421.— 90.  Methchnikoff.  See  Nos.  14  and  51.-91. 
NiEczAjEFF.  Verhandl.  das  X.  Internal.  Med.  Congress,  Berlin,  18itO,  ii,  pt.  3,  p. 
54. —  5)2.  Sanarelli.  Ctbl.  f.  Bakt.  x.  1891,  p.  .'514.-93.  Sternberg.  Am.  J.  of 
Med.  Sc.  April  1881.  —  For  the  abundant  literature  on  this  subject  consult  Bitter 
(No.  84)  and  Lubarsch  (No.  88),  as  also  the  full  bibliography  (up  to  1893)  given  by 
Sternberg  in  his  Manual  of  Bacteriology.  New  York,  1892,  and  (to  1895)  in  his  Iinmur 
nity,  Protective  Inoculation,  etc.    New  York,  1895. 


VIII.    Phagocytosis   in   Connection   with  Pathogenic   Microbes  of  Vabious 
Diseases  (for  Shortness  Names  of  Diseases  alone  given) 

Actinomycosis: — 94.  Marchand.  Eulcnburg's  liealencyclopudie,  article  "Actino- 
mycosis." —  95.  BosTKiiM.  Zeigler's  Beitr.  ix.  1890.  —  9(i.  Pawluwsky  and 
Maksukoff.  a.  de  I'Imt.  Pasteur,  vii.  1893,  p.  544.  Anthrax :— i)7.  Hess.  Virrh. 
Arch.  cix.  p.  .•565.-98.  Koch.  Cohn'a  Beitr.  z.  Biol,  der  Pflanzen,  ii.  1876.  — 9i). 
Lubarsch.  Fortschr.  d.  Med.  1888,  p.  4.  — 100.  Metschnikoff.  Virch.  Arch,  xcvii. 
p.  502.  and  A.  de  I'Inst.  Pasteur,  i.  1H87,  p.  7.-101.  Nutall.  Zeitschr.  f.  Hygiene, 
iv.  l>-;88.  — 102.  Petruschky.  Zeigler's  Beitr.  iii.  1888,  p.  357,  and  Fortschr.  d. 
Med.  viii.  1«90,  No.  15.  Cholera  :  — 103.  Metschnikoff.  A.  de  VI.  P.  viii.  185)4, 
p.  529.  —  104.  Pfeiffer  and  Wasserman.  Zeitschr.  f.  Hygiene,  xiv.  1893,  p.  55).  — 
105.  Cantacuzene.  Rtichcrrhrs  .inr  le  mode  de  destruction  du  Vibrinn  Cholerique. 
Paris,  1HS)4.  Diphtheria :  — KKJ.  GABRirrHEWSKi.  A.  de  VI.  P.  viii.  185H.  —  107. 
Massart.  See  No.  76.  Erysipelas  :  — 108.  Metschnikoff.  Virvh.  Arch.  evil.  1887, 
p.  209,  and  numerous  other  observers.     Gonorrhoea :  — 109.  Neissbr  and  all  subse- 


i!' 


S-! 


IN  FLA  MM  A  TION 


137 


qnent  observers  (for  bibliography  see  Sternberg).  Hog  Cholera :  — 110.  Metschnikoff. 
A.  de  VI.  P.  vi.  1802,  p.  '28'J.  Leprosy :  — 111.  Metschnikoff  aud  Soudakewitch. 
Virdi.  Arch.  cvii.  1887,  p.  228  (and  all  recent  observers).  Malaria:  — 112.  Gulgi. 
Guz.  degli  Ospitali,  1886,  No.  53  (parasites  in  leucocytes,  as  distinguished  from  red 
corpuscles).  Mouse  Septicsemia :  — 113.  Metschnikoff.  A.  de  I'Inst.  P.  v.  1891. 
Pathogenetic  Toruls  in  Daphnia :  — 114.  Metschnikoitf.  Virch.  Arch.  xcvi.  Patho- 
genic Moulds  (Aspergillus,  etc.) :  — 115.  Ribbkrt.  See  No.  G6.  Pneumonia  (Diplo- 
coccus) :  —  Ufi.  Gamaleia.  A.  de  VI.  P.  ii.  1888,  p.  445.  — 117.  Isaeff.  Ihid. 
vii.  18!)3,  p.  260.  — 118.  Tchistovitch.  Ibid.  iii.  1889,  p.  337.  Relapsing  Fever: 
— 11!>.  Metschnikoff.  Ihid.  i.  1887,  p.  329.  — 120.  Soudakewitch.  Ihid.  v. 
1891,  p.  545.  Suppuration  (Staphylococcus  pyogenes)  :  — 121.  Fleck.  Die  acute 
Entziindunn  der  Lunge.  Dissort.,  Bonn,  1886.  — 122.  Hess.  See  No.  37.  — 123.  Hohn- 
FELDT.  See  No.  38.  — 124.  Lahr.  Ueher  d.  Untergang  d.  Staph,  in  der  Lunge. 
Dissert.,  Bonn,  1887  (and  numerous  other  observers).  Swine  Erysipelas  ("Rouget" 
or  "  Rothlauf  ") :  — 125.  Metschnikoff.  A.  de  VL  P.  iii.  1889,  p.  289.  — 126.  Schiitz. 
Arh.  a.  d.  Kaiserl.  Qenundheitsumt,  i.  1885,  p.  61.  — 127.  Tchistovitch.  See  No.  118. 
Symptomatic  Anthrax  (Quarter-evil)  :  — 128.  Rcffeb.  li.  M.  J.  May  24th,  1890.  —  129. 
RuFFER.  A.  de  VI.  P.  v.  1891,  p.  673.  Tuberculosis :  — 130.  Bokrbl.  See  No.  58. — 
131.  Mktschnikoff.  See  No.  51.  — 132.  Stschastny.  Virch.  Arch.  cxv.  1889,  and  No. 
68.  Vibrio  Gamaleia  vel  Metschnikovi :  — 133.  Metschnikoff.  A.  de  VI.  Pasteur,  v. 
1891,  p.  465.  — 134.  Sanarelli.    /6td.  vii.  p.  225. 


IX.   On  the  Bactbricidal  Action  of  the  Bodily  Humours 

135.  Behrino  and  Nissen.  Zeitsehr.f.  Hygiene,  viii.  1890,  p.  424.  — 136.  Buchner. 
Arch./.  Hygiene,  x.  1890,  pts.  1  and  2 ;  Centrlhl.f.  Bakt.  v.  1889,  p.  817,  and  vi.  p.  1.  — 137. 
Emmerich  and  di  Mattel  Fortschr.  de  Med.  vi.  p.  729.  — 138.  Von  Fodor.  D.  Med. 
Woch.  1887,  p.  745;  and  Cthl.f.  Bakt.  vii.  18SK),  p.  753.  — 139.  Hankin.  See  No.  150.— 
140.  LuBARscH.  Cthl.f.  Bakt.  vi.  1889,  p.  ^Ul.  —141.  Nissen.  Zeitsehr.f.  Hygiene,  vi. 
1889,  p.  487.  — 142.  Nuttai  l.  Ibid.  iv.  18HR,  p.  ;*o,'<.  — 143.  Pekelharinq.  La  Sem.  mid. 
1892,  p.  503.  —  14t.  Tkaube  and  ijdCH l,eidb?:.  Jahresbr.  d.  Schlesischen  Gesell.  Iii.  1874, 
p.  179.-145.  Weigert.  Fortschr.  <i.  Med.  v.  18S7,  p.  733.  — For  other  articles  consult 
the  works  of  Sternberg  previous.'y  meutiou  ;d. 


X.  Upon  Extra-Cellular  Activity  and  the  Production  of  Bactericidal  and 
ToxiciDAL  Substances  from  Wandering  Cells,  etc. 

146.  Adami.  See  No.  82.-147.  Buchner.  Fortschr.  d.  Med.  x.  1892,  Nos.  9  and 
10;  Miinch.  Med.  Woch.  1894;  Ctbl.  f.  Bakt.  xvi.  1894,  p.  738,  and  No.  86.  — 148. 
Denys.  La  Cellule,  1894. —149.  Denys  and  Havel.  Arch,  de  mM.  exptlle.  vi.  1894.— 
150.  Hankin.  Proc.  Roy.  Soc.  xlviii.  18!K),  p.  93;  Ctbl.  f.  Bakt.  ix.  18{»2,  p.  722;  Ibid. 
vols.  xi.  and  xii. ;  see  also  No.  85.  — 151.  Kanthack  and  Hardy.  Proc.  Roy.  Soc. 
Nov.  1,  1892.-152.  Kanthack  and  Hardy.  J.  of  Physiol.  1893.  — 153.  Kanthack 
and  Hardy.  Phil.  Tram.  1894.-154.  Kosskl.  Zeitsehr.f.  Hygiew,  xvi.  1894.-155. 
Metschnikoff.  A.  de  VI.  P.  viii.  1894,  p.  70(5.  — 156.  Pfeiffeh.  Zeitsehr.f.  Hygiene, 
xvi.  18JI4,  p.  268,  and  xviii.  p.  1.  — 157.  Ribbert.  See  No.  65.  — 158.  TizzoNi  and  Cat- 
TANi.  Berl.klin.  JFocAeJwcAr.  3. 1894. — 159.  Vaughan  and  M'Clintock.  Med.  News 
(N.Y.),Dec.  23rd,  1893. 


XI.  On  the  Part  played  by  the  Blood  Vessels  in  Inflammation 


In  addition  to  Cohnheim  (No.  6),  Hamilton  (No.  9),  Leber  (No.  12),  Recklino- 
HAUSEN  (No.  16),  Samuel  (No.  18),  Weigert  (No.  23),  and  Zieoler  (No.  24),  consult 
—  KK).  Arnold.  Virch.  Arch.  liv.  1871,  on  "Development  of  Capillaries."  — Kil. 
Chakrin  and  Gley.  Arch,  de  Physiol.  Oct.  1890. —162.  Israel.  Lehrhuch  d.  Path. 
Anat.  —  HVA.  Samuel.  Virch.  Arch,  xliii.  18«i8,  p.  552,  and  li.  1870,  p.  178  ("Change 
in  Vessel  Wall,  inducing  slowing  of  Current ") .  — 164.  Thiersch.  Pithn  and  Billroth' s 
Chirurgie,  1867,  i.  i>t.  2,  p.  52?>  (on  "Now  Formation  of  Vessels").  —  Fuller  references 
given  iu  Ziegler  (No.  24)  and  Hamilton  (No.  9). 


137 


m 


SYSTEM  OF  MEDICINE 


XII.  On  the  Diapedesis  of  Leucocytes 

165.  Addison.  Exptl.  and  Pract.  Researches  upon  Infl.  London,  1843.  —  IGfi. 
Arnold.  Virch.  Arch.  Ivili.  1872,  Ixvi.  1874,  and  Ixviii.  1875. —I(i7.  Binz.  Virch. 
Arch,  lix.,  Ixziii.,  and  Ixxxix. ;  Arch./,  expt.  Path.  vii.  and  xiii.  —  1(W.  Cohnhkim. 
See  No.  6.  — 1()9.  Dissklhorst.  Virch.  Arch,  cxiii.  1888,  p.  108.  — 170.  Herino.  Wivn. 
Acad.  Bericht.  Ivii.  18()8,  p.  170  (on  the  "Adhesion  of  Corpuscles").  — 171.  Kalten- 
brunner.  Exp.  circa  stat.  sanguinis  et  tKisoruin  in  infl.  182(>.  — 172.  KErtNKR.  Pfliigcr's 
Archiv,  vii.  — 173.  Lavdowsky.  Virch.  Arch,  xevii.  — 174.  Mkthchnikoff.  See  No. 
14. —17.5.  Pekklharing.  F/rc/i.  ^?t^.  ci.  1886. —  170.  Re(ki,in(;ti  \u8BN.  Strieker's 
Hanilh.  Article,  "Das  Lymphfjefiisssysteni."  — 177.  Schki.ai  Pfli'iger's  Arch. 

i.  18()8,  pp.  ()03  and  (»7.  — 178.  Thoma.    lierl.  klin.  IFoc/t.  18>  u.  Waller.    Phil. 

Mag.  xxix.  184G,  pp.  217,  2!)8,  3«7. 

(a)  On  THE  Effect  of  Intra  and  Extra- Vascular  "T(  un       ui-  in  Diapedesis 

180.  Bouchard.  Esxni  d'une  thiorie  de  V infection.  Verhandl.  d.  X.  Internat. 
Med.  Congr.  Berlin,  18!K).  — 181.  Chakrin.  Ibid.  ii.  pt.  ;<,  p.  29.  — 182.  Roger. 
Cnntrib.  a  V4tude  de  I'ininiuii.  acquire,  p.  1.  —  18;i.  Ruffku.  A.  de  I'l.  P.  v.  IHid, 
p.  673.  —  The  earlier  literature  of  diapedesis  is  fjiven  in  detail  by  WA(iNER  (No.  22) 
and  Hamilton  (No.  9).  The  last  (German)  edition  of  Ziegler  (No.  24)  is  also  very 
full. 

Xin.  On  thk  Part  played  by  the  Nervous  System  in  Inflammation 

184.  Berkley.  Anat.  Anz.  viii.  1893.  Nos.  23  and  24,  and  ix.  1893,  Nos.  1  and 
2;  Joum.  of  Cotnp.  Neurol,  iii.  1893,  p.  107;  Pathol.  Studies,  Johns  Hopkins  Univ., 
Neurology,  ii.  1894  ("Upon  Nerve  Entlings  in  Vessel  Walls,  etc.").  — 18.").  Charcot. 
Le(;ons  .curies  maladies  du  syvt.  nerveux.  Paris,  1873,  p.  lOiJ.  — 18(1.  Cohnhkim.  See 
No.  6.-187.  Dache  and  Malvoz.  A.  de  VI.  P.  vi.  1892,  p.  5;!8  (on  "Influence  of 
Nervous  System  in  Mycotic  InHammations").  — 188.  De  I'volis.  IVifonna  Medica, 
1889,  No.  200.  — 189.  Frenkel.  Arch.  d.  med.  expt.  iv.  1892,  p.  ()38.  — 190.  (JEiuiENS. 
Pfliiger's  Arch.  xiii.  p.  591.  — 191.  Kt.kbs.  Allg.  Pathol,  ii.  1889,  p.  384.  — 192.  Len- 
HossEK.  Arch.  f.  mikr.  Anat.  xxxix.  1892  (on  " Nerve  Endings").  — 193.  Mitchell, 
S.  Weir.  Injuries  of  Nerves.  I'hila.  1872,  p.  108.  — 19+.  Ochotine.  Arch,  de  ni^d. 
expt.  iv.  1892,  p.  245.  — 19.").  Retzius.  Biol.  Untersuchungen,  Neue  Foljje,  iii.  1891, 
p.  49,  and  iv.  — 19(!.  Roger.  Comptes  Bend.  Soc.  de  Biol.  3rd  May  1890,  and  22nd 
Nov.  1890.-197.  Rijti,mb:yer.  Arch.  f.  e.rpt.  Pathol,  xiv.  p.  3.V4.  — 198.  Samuel. 
Virch.  Arch.  cxxi.  — 199.  Saviotti.  Virch.  Arch.  1.  1870,  p.  .592  (on  "Dilation  and 
Contraction  of  Arteries  accordinji  to  Nature  of  Irritant"). — 2(X).  Severini.  La  con- 
trattilita  dei  capillari,  1881.  —  201.  Wagner,  A.  Arch.  f.  kiln.  Chirurg.  xi.  1869, 
p.  1. 

XIV.  On  the  Part  played  by  the  Connective  Tissue  Cells  in  Inflammation 


202.  Arnold.  Arch.  f.  Mikr.  Anat.  xxx.  1887. — 203.  Baumoarten.  Virch. 
Arch.  Ixxviii.  1879;  Ueber  Tuherkel  und  Tuberkulose,  i.  Die  Ilistogenese  des  Taber- 
kulosenprocesses.  Berlin,  1885. — 204.  Bourel.  See  No.  .58. — 205.  Cokn.  Ziegler's 
Beitr.  ii.  1887.— 206.  Cornil  and  Ranvier.  See  No.  7.-207.  Discussion  at  the 
Tenth  Internat.  Med.  Cong.  Berlin,  1890.  (Ziegler,  Marchand,  Grawit/.)  Verhmnll. 
ii.  pt.  3,  p.  1.  —  208.  Fischer.  Untersuch.  ii.  die  11  dung  von  Schnittvunden  dcr  Ilant. 
Inaug.  Diss.  Tubingen,  1888.— 209.  Flemming.  Virch.  Arch.  Ivi.  1872,  p.  IKi. 
—  210.  Grawitz.  D.  Med.  Wochenschr.  1889.  No.  2.3,  on  "  Slumbering  Cell8."  —  211. 
Grawitz.  Virch.  Arch,  cxviii.  1889.-212.  (Jriffith,  J.  ,/.  of  Pathol,  ii.  18!t4 
(on  "Development  of  Wandering  from  Fixed  Cells").  —  213.  Gull  and  Sutton.  Med.- 
Chir.  Trans.  Iv.  1872,  p.  273. —214.  Huchakd.  Traits  des  maladies  du  cteur.  Paris, 
1889  (on  "Dystrophic  Sclerosis").- 21.5.  Krafkt.  Zi^gl.  Beitr.  1.  1884.-216. 
JLiRCHAND,  Ibid.  iv.  1888.-217.  Metschnikoff.  Hini.  Cenfrbl.  1883,  p.  5lil : 
A.  de  VI.  P.  vi.  1892,  p.  1  (im  "  nevclopmeiit  of  Wandering  from  Fi.xed  Cells  ").— 218. 
NiKiFOROFF.     Ziegl.  Beitr.   viii.    1890,    p.  419.-219.    Podwyssozki.    Ibid.  i.  1884, 


THE  DOCTRINE    OF  FEVER 


•39 


and  ii.  188C.  —  220.  Ranvieh.  Comptcs  rend,  de  I' Acad.  d.  Kc.  1891,  p.  843. —221. 
Rkinkk.     Zie(/l.  Beitr.  v.  1,S8'.>.  —  222.  Roy  and  Apami.    B.  M.  J.  15th  Dec.   1888. 

—  22;{.  ScHKLTKMA.  D.  Med.  Woch.  1887,  p.  4t}3.  —  224.  Shekrinoton  and  Ballance. 
J.  of  Physiol.  188i),  p.  85f).  — 22;').  Soudakewitch.  A.  de  I'l.  P.  vi.  18!»2,  p.  13. — 
220.  Stkicker.  atudirn  a.  d.  Inst./,  exp.  Pathol.  Vienna,  i.  1870.  —  227.  TourET. 
Des  modifications  cellul.  dans  I'inft.  simple  du  pcritoine.  Thesis,  Paris,  1887. — 228. 
ZiBOLKR.  Ej-p.  Untersuch.  ii.  die  Herkutift  der  Tuberkelelement.  Wiirzburg,  1875. 
— 229.  ZiEGLKR.  Untersuch.  ii.  pathol.  Bindgewebs-  und  Ge/iissnenbildung.  Wnrz- 
burg,  187(). — 230.  Grawitz,  No.  211,  gives  a  very  full  bibliography  up  to  1889  of  the 
part  played  by  the  connective  tissue  cells.  Consult  also  Virchow  (No.  21),  Cohnheim 
(()),  Metschnikoff  (14),  and  Zieglkr  (24).  The  later  German  editions  of  Zir(/l/'r's 
Handbook  contain  a  very  judicial  discussion  of  the  relationship  of  librous  hyperplasia 
to  iutlammation. 

XV.    On   the  TEMPERATtTRE  CHANGES  IN   INFLAMED   ArEAS 

231.  Billroth  and  Hufschmipt.    Arch.  f.  klin.  Chirurg.  vi.  1804,  p.  373.-232. 
Hunter,  John.    On  the  Blood,  Inflammation,  and  Gunshot  Wounds.    London,  1793. 

—  233.  HuppKRT.  Arch.  d.  Ildlkuiide,  xiv.  1873,  p.  73.  —  2.'54.  Jacobson  and  Bkrn- 
H.\RDT.  M<d.  Ccntlbl.  18fJ9,  No.  19.  —  2;V>.  Laupien.  Ibid.  18G9,  No.  19.  —  2;«i. 
Schneider.  Ibid.  1870,  No.  34.-237.  Simon.  Ilolmrs's  System  of  Surgery,  1860, 
article  "  Iiiflammatiou."  —  238.  Weber,  O.    IJeutsch.  Klin.  1864,  Nos.  43  and  44. 


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